Статті в журналах: "Central nervous system-associated macrophages"

1

Poppell, Michael, Grace Hammel, and Yi Ren. "Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases." International Journal of Molecular Sciences 24, no. 6 (March 21, 2023): 5925. http://dx.doi.org/10.3390/ijms24065925.

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Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune disorders. How these cells may be contributing to the adaptive immune response and potentially perpetuating the progression of neurodegenerative diseases and neural injuries is not fully understood. Within this review, we hope to illustrate the role that macrophages and microglia play as initiators of adaptive immune response in various CNS diseases by offering evidence of: (1) the types of immune responses and the processes of antigen presentation in each disease, (2) receptors involved in macrophage/microglial phagocytosis of disease-related cell debris or molecules, and, finally, (3) the implications of macrophages/microglia on the pathogenesis of the diseases.

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2

Prinz, Marco, Takahiro Masuda, Michael A. Wheeler, and Francisco J. Quintana. "Microglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation." Annual Review of Immunology 39, no. 1 (April 26, 2021): 251–77. http://dx.doi.org/10.1146/annurev-immunol-093019-110159.

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The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.

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3

Yamasaki, Ryo, Haiyan Lu, Oleg Butovsky, Nobuhiko Ohno, Anna M. Rietsch, Ron Cialic, Pauline M. Wu, et al. "Differential roles of microglia and monocytes in the inflamed central nervous system." Journal of Experimental Medicine 211, no. 8 (July 7, 2014): 1533–49. http://dx.doi.org/10.1084/jem.20132477.

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In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell–mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

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4

King, Irah L., Travis L. Dickendesher, and Benjamin M. Segal. "Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease." Blood 113, no. 14 (April 2, 2009): 3190–97. http://dx.doi.org/10.1182/blood-2008-07-168575.

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Abstract Mature myeloid cells (macrophages and CD11b+ dendritic cells) form a prominent component of neuroinflammatory infiltrates in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). The mechanism by which these cells are replenished during relapsing and chronic neuroinflammation is poorly understood. Here we demonstrate that CD11b+CD62L+Ly6Chi monocytes with colony-forming potential are mobilized into the bloodstream by a granulocyte-macrophage colony-stimulating factor-dependent pathway immediately before EAE relapses. Circulating Ly6Chi monocytes traffic across the blood-brain barrier, up-regulate proinflammatory molecules, and differentiate into central nervous system dendritic cells and macrophages. Enrichment of Ly6Chi monocytes in the circulating pool is associated with an earlier onset and increased severity of clinical EAE. Our studies indicate that granulocyte-macrophage colony-stimulating factor–driven release of Ly6Chi precursors from the bone marrow prevents exhaustion of central nervous system myeloid populations during relapsing or chronic autoimmune demyelination, suggesting a novel pathway for therapeutic targeting.

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5

Katsumoto, Atsuko, Haiyan Lu, Aline S. Miranda, and Richard M. Ransohoff. "Ontogeny and Functions of Central Nervous System Macrophages." Journal of Immunology 193, no. 6 (September 5, 2014): 2615–21. http://dx.doi.org/10.4049/jimmunol.1400716.

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6

Perry, V. Hugh, Peter-Brian Andersson, and Siamon Gordon. "Macrophages and inflammation in the central nervous system." Trends in Neurosciences 16, no. 7 (July 1993): 268–73. http://dx.doi.org/10.1016/0166-2236(93)90180-t.

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7

Piani, D., DB Constam, K. Frei, and A. Fontana. "Macrophages in the Brain: Friends or Enemies?" Physiology 9, no. 2 (April 1, 1994): 80–84. http://dx.doi.org/10.1152/physiologyonline.1994.9.2.80.

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Cells of the macrophage lineage are ubiquitously distributed in the body, including the central nervous system. They represent an essential host defense system to protect from infections. However, recent evidence indicates that brain macrophages may also be responsible for tissue destruction, including loss of neurons and demyelination.

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8

Tran, E. H., K. Hoekstra, N. van Rooijen, C. D. Dijkstra, and T. Owens. "Macrophages modulate immune invasion of the central nervous system." Journal of Neuroimmunology 90, no. 1 (September 1998): 22. http://dx.doi.org/10.1016/s0165-5728(98)91310-8.

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9

Sminia, T., C. J. A. De Groot, C. D. Dijkstra, J. C. Koetsier, and C. H. Polman. "Macrophages in the central nervous system of the rat." Immunobiology 174, no. 1 (January 1987): 43–50. http://dx.doi.org/10.1016/s0171-2985(87)80083-9.

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10

Couraud, Pierre-Olivier. "Interactions between lymphocytes, macrophages, and central nervous system cells." Journal of Leukocyte Biology 56, no. 3 (September 1994): 407–15. http://dx.doi.org/10.1002/jlb.56.3.407.

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11

Trebst, Corinna, Susan M. Staugaitis, Pia Kivisäkk, Don Mahad, Martha K. Cathcart, Barbara Tucky, Tao Wei, et al. "CC Chemokine Receptor 8 in the Central Nervous System Is Associated with Phagocytic Macrophages." American Journal of Pathology 162, no. 2 (February 2003): 427–38. http://dx.doi.org/10.1016/s0002-9440(10)63837-0.

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12

Perry, V. H., P. R. Crocker, and S. Gordon. "The blood-brain barrier regulates the expression of a macrophage sialic acid-binding receptor on microglia." Journal of Cell Science 101, no. 1 (January 1, 1992): 201–7. http://dx.doi.org/10.1242/jcs.101.1.201.

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In vitro the expression of a sialic acid-binding receptor on murine macrophages, sialoadhesin, is regulated by exposure to an inducing agent present in serum. We have used immunocytochemistry to examine the macrophage populations of the nervous system in order to test whether this serum inducing agent (SIA) also regulates sialoadhesin expression in vivo and whether plasma proteins may influence the phenotype of macrophages of the nervous system. Microglia, the resident macrophages of the central nervous system, reside behind the blood-brain barrier and do not express sialoadhesin. Microglia and macrophage populations in the cicumventricular organs, choroid plexus and leptomeninges are exposed to plasma proteins and some macrophages express sialoadhesin at these sites. Injury to the CNS, which damages the blood-brain barrier, induces sialoadhesin expression on a proportion of macrophages and microglia within the parenchyma. The expression of sialoadhesin matches the temporal and spatial distribution of the plasma extravasation into the brain parenchyma. These experiments show that exposure to SIA is necessary for sialoadhesin expression and lend further support to the idea that the phenotype of microglia is in part regulated by the presence of the blood-brain barrier.

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13

Plemel, Jason R., Jo Anne Stratton, Nathan J. Michaels, Khalil S. Rawji, Eric Zhang, Sarthak Sinha, Charbel S. Baaklini, et al. "Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion." Science Advances 6, no. 3 (January 2020): eaay6324. http://dx.doi.org/10.1126/sciadv.aay6324.

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Microglia and infiltrating macrophages are thought to orchestrate the central nervous system (CNS) response to injury; however, the similarities between these cells make it challenging to distinguish their relative contributions. We genetically labeled microglia and CNS-associated macrophages to distinguish them from infiltrating macrophages. Using single-cell RNA sequencing, we describe multiple microglia activation states, one of which was enriched for interferon associated signaling. Although blood-derived macrophages acutely infiltrated the demyelinated lesion, microglia progressively monopolized the lesion environment where they surrounded infiltrating macrophages. In the microglia-devoid sciatic nerve, the infiltrating macrophage response was sustained. In the CNS, the preferential proliferation of microglia and sparse microglia death contributed to microglia dominating the lesion. Microglia ablation reversed the spatial restriction of macrophages with the demyelinated spinal cord, highlighting an unrealized macrophages-microglia interaction. The restriction of peripheral inflammation by microglia may be a previously unidentified mechanism by which the CNS maintains its “immune privileged” status.

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14

Munro, David A. D., Barry M. Bradford, Samanta A. Mariani, David W. Hampton, Chris S. Vink, Siddharthan Chandran, David A. Hume, Clare Pridans, and Josef Priller. "CNS macrophages differentially rely on an intronic Csf1r enhancer for their development." Development 147, no. 23 (December 1, 2020): dev194449. http://dx.doi.org/10.1242/dev.194449.

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ABSTRACTThe central nervous system hosts parenchymal macrophages, known as microglia, and non-parenchymal macrophages, collectively termed border-associated macrophages (BAMs). Microglia, but not BAMs, were reported to be absent in mice lacking a conserved Csf1r enhancer: the fms-intronic regulatory element (FIRE). However, it is unknown whether FIRE deficiency also impacts BAM arrival and/or maintenance. Here, we show that macrophages in the ventricular system of the brain, including Kolmer's epiplexus macrophages, are absent in Csf1rΔFIRE/ΔFIRE mice. Stromal choroid plexus BAMs are also considerably reduced. During normal development, we demonstrate that intracerebroventricular macrophages arrive from embryonic day 10.5, and can traverse ventricular walls in embryonic slice cultures. In Csf1rΔFIRE/ΔFIRE embryos, the arrival of both primitive microglia and intracerebroventricular macrophages was eliminated, whereas the arrival of cephalic mesenchyme and stromal choroid plexus BAMs was only partially restricted. Our results provide new insights into the development and regulation of different CNS macrophage populations.

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15

Katsetos, Christos D., John E. Fincke, Agustin Legido, Harold W. Lischner, Jean-Pierre de Chadarevian, Edward M. Kaye, Chris D. Platsoucas, and Emilia L. Oleszak. "Angiocentric CD3+ T-Cell Infiltrates in Human Immunodeficiency Virus Type 1-Associated Central Nervous System Disease in Children." Clinical Diagnostic Laboratory Immunology 6, no. 1 (January 1, 1999): 105–14. http://dx.doi.org/10.1128/cdli.6.1.105-114.1999.

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ABSTRACT A significant proportion of brain tissue specimens from children with AIDS show evidence of vascular inflammation in the form of transmural and/or perivascular mononuclear-cell infiltrates at autopsy. Previous studies have shown that in contrast to inflammatory lesions observed in human immunodeficiency virus type 1 (HIV-1) encephalitis, in which monocytes/macrophages are the prevailing mononuclear cells, these infiltrates consist mostly of lymphocytes. Perivascular mononuclear-cell infiltrates were found in brain tissue specimens collected at autopsy from five of six children with AIDS and consisted of CD3+ T cells and equal or greater proportions of CD68+ monocytes/macrophages. Transmural (including endothelial) mononuclear-cell infiltrates were evident in one patient and comprised predominantly CD3+ T cells and small or, in certain vessels, approximately equal proportions of CD68+monocytes/macrophages. There was a clear preponderance of CD3+ CD8+ T cells on the endothelial side of transmural infiltrates. In active lesions of transmural vasculitis, CD3+ T-cell infiltrates exhibited a distinctive zonal distribution. The majority of CD3+ cells were also CD8+ and CD45RO+. Scattered perivascular monocytes/macrophages in foci of florid vasculitis were immunoreactive for the p24 core protein. In contrast to the perivascular space, the intervening brain neuropil was dominated by monocytes/macrophages, microglia, and reactive astrocytes, containing only scant CD3+ CD8+ cells. Five of six patients showed evidence of calcific vasculopathy, but only two exhibited HIV-1 encephalitis. One patient had multiple subacute cerebral and brainstem infarcts associated with a widespread, fulminant mononuclear-cell vasculitis. A second patient had an old brain infarct associated with fibrointimal thickening of large leptomeningeal vessels. These infiltrating CD3+ T cells may be responsible for HIV-1-associated CNS vasculitis and vasculopathy and for endothelial-cell injury and the opening of the blood-brain barrier in children with AIDS.

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16

Lazarov‐Spiegler, Orly, Arieh S. Solomon, Adi Ben Zeev‐Brann, David L. Hirschberg, Vered Lavie, and Michal Schwartz. "Transplantation of activated macrophages overcomes central nervous system regrowth failure." FASEB Journal 10, no. 11 (September 1996): 1296–302. http://dx.doi.org/10.1096/fasebj.10.11.8836043.

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17

Franco, Rafael, and Diana Fernández-Suárez. "Alternatively activated microglia and macrophages in the central nervous system." Progress in Neurobiology 131 (August 2015): 65–86. http://dx.doi.org/10.1016/j.pneurobio.2015.05.003.

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18

Leskovar, A., L. J. Moriarty, J. J. Turek, I. A. Schoenlein, and R. B. Borgens. "The macrophage in acute neural injury: changes in cell numbers over time and levels of cytokine production in mammalian central and peripheral nervous systems." Journal of Experimental Biology 203, no. 12 (June 15, 2000): 1783–95. http://dx.doi.org/10.1242/jeb.203.12.1783.

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We evaluated the timing and density of ED-1-positive macrophage accumulation (ED 1 is the primary antibody for the macrophage) and measured cytokine production by macrophages in standardized compression injuries to the spinal cord and sciatic nerves of individual rats 3, 5, 10 and 21 days post-injury. The actual site of mechanical damage to the nervous tissue, and a more distant site where Wallerian degeneration had occurred, were evaluated in both the peripheral nervous system (PNS) and the central nervous system (CNS) at these time points. The initial accumulation of activated macrophages was similar at both the central and peripheral sites of damage. Subsequently, macrophage densities at all locations studied were statistically significantly higher in the spinal cord than in the sciatic nerve at every time point but one. The peak concentrations of three cytokines, tumor necrosis factor α (TNF α), interleukin-1 (IL-1) and interleukin-6 (IL-6), appeared earlier and were statistically significantly higher in injured spinal cord than in injured sciatic nerve. We discuss the meaning of these data relative to the known differences in the reparative responses of the PNS and CNS to injury.

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19

Elchaninov, Andrey, Anastasia Lokhonina, Maria Nikitina, Polina Vishnyakova, Andrey Makarov, Irina Arutyunyan, Anastasiya Poltavets, et al. "Comparative Analysis of the Transcriptome, Proteome, and miRNA Profile of Kupffer Cells and Monocytes." Biomedicines 8, no. 12 (December 18, 2020): 627. http://dx.doi.org/10.3390/biomedicines8120627.

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Macrophage populations in most mammalian organs consist of cells of different origin. Resident macrophages originate from erythromyeloid precursors of the yolk sac wall; maintenance of the numbers of such macrophages in postnatal ontogenesis is practically independent of bone marrow haematopoiesis. The largest populations of the resident macrophages of embryonic origin are found in the central nervous system (microglia) and liver (Kupffer cells). In contrast, skin dermis and mucous membranes become predominantly colonized by bone marrow-derived monocytes that show pronounced functional and phenotypic plasticity. In the present study, we compared Kupffer cells and monocytes using the immunophenotype, gene expression profile, proteome, and pool of microRNA. The observed differences did not consider the resident liver macrophages as purely M2 macrophages or state that monocytes have purely M1 features. Monocytes show signs of high plasticity and sensitivity to pathogen-associated molecular patterns (e.g., high levels of transcription for Tlr 2, 4, 7, and 8). In contrast, the resident liver macrophages were clearly involved in the regulation of specific organ functions (nitrogen metabolism, complement system protein synthesis).

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20

Kennedy, David W., and Janis L. Abkowitz. "Kinetics of Central Nervous System Microglial and Macrophage Engraftment: Analysis Using a Transgenic Bone Marrow Transplantation Model." Blood 90, no. 3 (August 1, 1997): 986–93. http://dx.doi.org/10.1182/blood.v90.3.986.

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Abstract To determine the kinetics of tissue macrophage and microglial engraftment after bone marrow (BM) transplantation, we have developed a model using the ROSA 26 mouse. Transplanted ROSA 26 cells can be precisely identified in recipient animals because they constitutively express β-galactosidase (β-gal) and neomycin resistance. B6/129 F2 mice were irradiated and transplanted with BM from ROSA 26 donors and their tissues (spleen, marrow, brain, liver, and lung) examined at various time points to determine the kinetics of engraftment. Frozen sections from transplanted animals were stained histochemically for β-gal to identify donor cells. At 1, 2, 6, and 12 months posttransplantation, 98% to 100% of granulocyte-macrophage colonies were of donor (ROSA 26) origin determined by β-gal staining and by neomycin resistance. Splenic monocytes/macrophages were 89% donor origin by 1 month confirming quick and complete engraftment of hematopoietic tissues. At this time, only rare ROSA 26 tissue macrophages or microglia were observed. Alveolar macrophage engraftment was evident by 2 months and had increased to 61% of total tissue macrophages at 1 year posttransplantation. The kinetics of liver Kupffer cell engraftment were similar to those seen in the lung. However, donor microglial engraftment remained only 23% of total microglia at 6 months and increased to only 30% by 1 year. Also, donor microglia were predominantly seen at perivascular and leptomeningeal, and not parenchymal, sites. The data show that microglia derive from BM precursors but turn over at a significantly slower rate than other tissue macrophages. No clinical or histological graft-versus-host disease was observed in the recipients of ROSA 26 BM. These kinetics may impact strategies for the gene therapy of lysosomal storage diseases. Because individual donor cells can be identified in situ, the ROSA 26 model should have many applications in transplantation biology including studies of homing and differentiation.

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21

Kennedy, David W., and Janis L. Abkowitz. "Kinetics of Central Nervous System Microglial and Macrophage Engraftment: Analysis Using a Transgenic Bone Marrow Transplantation Model." Blood 90, no. 3 (August 1, 1997): 986–93. http://dx.doi.org/10.1182/blood.v90.3.986.986_986_993.

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To determine the kinetics of tissue macrophage and microglial engraftment after bone marrow (BM) transplantation, we have developed a model using the ROSA 26 mouse. Transplanted ROSA 26 cells can be precisely identified in recipient animals because they constitutively express β-galactosidase (β-gal) and neomycin resistance. B6/129 F2 mice were irradiated and transplanted with BM from ROSA 26 donors and their tissues (spleen, marrow, brain, liver, and lung) examined at various time points to determine the kinetics of engraftment. Frozen sections from transplanted animals were stained histochemically for β-gal to identify donor cells. At 1, 2, 6, and 12 months posttransplantation, 98% to 100% of granulocyte-macrophage colonies were of donor (ROSA 26) origin determined by β-gal staining and by neomycin resistance. Splenic monocytes/macrophages were 89% donor origin by 1 month confirming quick and complete engraftment of hematopoietic tissues. At this time, only rare ROSA 26 tissue macrophages or microglia were observed. Alveolar macrophage engraftment was evident by 2 months and had increased to 61% of total tissue macrophages at 1 year posttransplantation. The kinetics of liver Kupffer cell engraftment were similar to those seen in the lung. However, donor microglial engraftment remained only 23% of total microglia at 6 months and increased to only 30% by 1 year. Also, donor microglia were predominantly seen at perivascular and leptomeningeal, and not parenchymal, sites. The data show that microglia derive from BM precursors but turn over at a significantly slower rate than other tissue macrophages. No clinical or histological graft-versus-host disease was observed in the recipients of ROSA 26 BM. These kinetics may impact strategies for the gene therapy of lysosomal storage diseases. Because individual donor cells can be identified in situ, the ROSA 26 model should have many applications in transplantation biology including studies of homing and differentiation.

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22

Barbero-Aznarez, Pablo, Ramon Perez-Tanoira, Daniel Aguirre-Mollehuanca, Alvaro Trascasa-Caño, Jose Fortes-Alen, Felix Manzarbeitia-Arrambari, Jorge Castillo-Alvarez, Julia Montoya-Bordon, Elizabet Petkova-Saiz, and Laura Prieto-Perez. "Isolated central nervous system Whipple disease." Surgical Neurology International 13 (October 21, 2022): 477. http://dx.doi.org/10.25259/sni_591_2022.

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Background: Whipple disease (WD) is an infection caused by Tropheryma whipplei, which might present in three different forms: classical, localized, and isolated in the central nervous system (CNS). Methods: We report the result of a systematic review of the literature on WD unusually presenting with exclusively neurological symptoms, including two previously unpublished cases. A description of two cases with isolated CNS WD was performed, as well as a literature search in Cochrane, Scielo, and PubMed. Results: Two male adult patients presented with exclusively neurological symptomatology. Both magnetic resonance imaging (MRI) showed an intracranial mass suggestive of brain tumor. The histopathological examination was consistent with WD, with no systemic involvement. In the review of the literature, 35 cases of isolated CNS WD were retrieved. The median age at diagnosis was 43.5 (IQR 31.5–51.5). In 13 patients, the MRI showed a brain mass consistent with a brain tumor. The most common finding in the biopsy was the periodic-acid Schiff-stained foamy macrophages. Only five cases presented the pathognomonic sign of oculomasticatory myorhythmia. Thirteen cases had an adverse outcome that resulted in death during follow-up, whereas another 13 improved. The other nine patients remained stable or presented moderate improvement. Conclusion: Isolated CNS WD is a rare disease that should be considered among the differential diagnosis of CNS mass lesions. Brain biopsy is necessary to establish the diagnosis. It is stressed in the literature that an extended antibiotic course is required to prevent relapses and to control the disease.

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Lin, Adora A., Pulak K. Tripathi, Allyson Sholl, Michael B. Jordan, and David A. Hildeman. "Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production." Journal of Virology 83, no. 17 (June 10, 2009): 8604–15. http://dx.doi.org/10.1128/jvi.02477-08.

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ABSTRACT Intracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-γ). Here, we assessed the role of CD4+ T cells and IFN-γ on immune cell recruitment and proinflammatory cytokine/chemokine production in the central nervous system (CNS) after i.c. LCMV infection. We found that T-cell-depleted mice had decreased recruitment of hematopoietic cells to the CNS and diminished levels of IFN-γ, CCL2 (MCP-1), CCL3 (MIP-1α), and CCL5 (RANTES) in the cerebrospinal fluid (CSF). Mice deficient in IFN-γ had decreased CSF levels of CCL3, CCL5, and CXCL10 (IP-10), and decreased activation of both resident CNS and infiltrating antigen-presenting cells (APCs). The effects of IFN-γ signaling on macrophage lineage cells was assessed using transgenic mice, called “macrophages insensitive to interferon gamma” (MIIG) mice, that express a dominant-negative IFN-γ receptor under the control of the CD68 promoter. MIIG mice had decreased levels of CCL2, CCL3, CCL5, and CXCL10 compared to controls despite having normal numbers of LCMV-specific CD4+ T cells in the CNS. MIIG mice also had decreased recruitment of infiltrating macrophages and decreased activation of both resident CNS and infiltrating APCs. Finally, MIIG mice were significantly protected from LCMV-induced anorexia and weight loss. Thus, these data suggest that CD4+ T-cell production of IFN-γ promotes signaling in macrophage lineage cells, which control (i) the production of proinflammatory cytokines and chemokines, (ii) the recruitment of macrophages to the CNS, (iii) the activation of resident CNS and infiltrating APC populations, and (iv) anorexic weight loss.

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Guerau-De-Arellano, Mireia, Kyle Jablonski, Stephanie Amici, and Phillip Popovich. "Identification of polarized macrophage signatures (INM1P.439)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 56.16. http://dx.doi.org/10.4049/jimmunol.194.supp.56.16.

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Abstract Pro-inflammatory (M1) macrophages are implicated in inflammatory diseases while pro-regenerative (M2) macrophages may be beneficial in Central Nervous System disorders. To modulate these phenotypes for therapeutic purposes, we need further understanding of the signaling pathways that define and distinguish M1 versus M2 macrophages. Here, we investigated the signature, i.e., the patterns of gene up/down-regulation, associated with mouse M1 and M2 polarized macrophages through cDNA microarray. The M1 macrophage signature was formed by 629 up-regulated and 732 down-regulated genes while M2 macrophage up-regulated 388 genes and down-regulated 425 genes. Additional analyses revealed that differentiation into M1 or M2 macrophages shared 81 up-regulated and 125 down-regulated genes which we consider to be linked to macrophage activation. In contrast, we identified 548 genes unique to M1 and 307 genes unique to M2 macrophages, including canonical markers previously used to distinguish phenotypes. While some of these genes have been previously identified, novel candidate M1/M2 markers were identified and validated by Real-Time PCR analysis of independent datasets. Our data reveals that macrophage differentiation into opposing M1/M2 phenotypes is formed by a combination of common and distinct genes expression patterns and provides novel genes as candidate differential markers and therapeutic targets.

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Schafernak, Kristian, Emma Utagawa, Shwetal Mehta, Tiffany Di Modica, Elliott Mufson, and Sylvia Perez. "PDTM-14. INTERACTIONS BETWEEN IMMUNE MICROENVIRONMENT, STEM CELLS, AND CELL PROLIFERATION IN PEDIATRIC EMBRYONAL CENTRAL NERVOUS SYSTEM [CNS] TUMORS." Neuro-Oncology 21, Supplement_6 (November 2019): vi189—vi190. http://dx.doi.org/10.1093/neuonc/noz175.790.

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Abstract Mounting evidence suggests the brain’s own immune cells, microglia, and perivascular macrophages play important roles in immune surveillance/inflammation, but also support proliferation/growth of gliomas, possibly through interactions with tumor stem cells. Immune cells are increasingly regarded as potential targets for cancer therapy, however, the immune microenvironment has not been well-studied in pediatric embryonal CNS tumors. In a series of 13 medulloblastomas, 7 PNETs and 6 ATRTs, we quantified the number of cells immunopositive for macrophage/microglia Ionizing calcium binding adaptor molecule 1 [Iba1], CD68 (expressed on both “M1” antitumor/proinflammatory macrophages and “M2” protumor/anti-inflammatory macrophages), CD163 (“M2” macrophages), CD3 (T-cell marker), CD4 (helper T cell), CD8 (cytotoxic T cell) and CD20 (B-cell marker) and correlated these findings with the stem-cell marker nestin and the Ki67/MIB1 proliferation index. Significant results were as follows: Across groups, CD68 showed a strong Spearman rank-order correlation with both CD163 (r=0.610, p=0.0007) and nestin (r=0.577, p=0.0017), while CD3 correlated strongly with CD8 (r=0.601, p=0.004), CD4 (r=0.526, p=0.005) and CD20 (r=0.499, p=0.008). Between groups, the number of CD163-positive cells was significantly higher in PNETs compared to medulloblastomas (p=0.035). Within the medulloblastoma group, CD68 showed a significant relationship with nestin (r=0.595, p=0.0387) and Ki67 (r=0.606, p=0.0333), and there was a robust correlation between CD4 and CD8 values (r=0.846, p=0.0000002). Within PNETs, there was a strong negative correlation between CD163 and nestin (r=-0.883, p=0.0000002), while CD68 correlated with CD4 (r=0.803, p=0.006). Within ATRTs, nestin and Ki67 were strongly correlated (r=1.000, p=0.0028) as were CD68 and CD163 (r=0.943, p=0.017). These data suggest a role for blocking embryonal CNS tumor-associated macrophages by inhibiting the CSF1R pathway (perhaps in conjunction with CD8-positive T cells which could antagonize the immunosuppressive function of tumor-associated macrophages) or reprogramming them from an M2 to an M1 phenotype (particularly in PNETs, which had the highest number of CD163-positive cells).

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Chen, Ye, Dongqiong Xiao, and Xihong Li. "Lactylation and Central Nervous System Diseases." Brain Sciences 15, no. 3 (March 11, 2025): 294. https://doi.org/10.3390/brainsci15030294.

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As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer’s disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.

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HEYES, Melvyn P., Cristian L. ACHIM, Clayton A. WILEY, Eugene O. MAJOR, Kuniaki SAITO, and Sanford P. MARKEY. "Human microglia convert l-tryptophan into the neurotoxin quinolinic acid." Biochemical Journal 320, no. 2 (December 1, 1996): 595–97. http://dx.doi.org/10.1042/bj3200595.

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Immune activation leads to accumulations of the neurotoxin and kynurenine pathway metabolite quinolinic acid within the central nervous system of human patients. Whereas macrophages can convert l-tryptophan to quinolinic acid, it is not known whether human brain microglia can synthesize quinolinic acid. Human microglia, peripheral blood macrophages and cultures of human fetal brain cells (astrocytes and neurons) were incubated with [13C6]l-tryptophan in the absence or presence of interferon γ. [13C6]Quinolinic acid was identified and quantified by gas chromatography and electron-capture negative-chemical ionization mass spectrometry. Both l-kynurenine and [13C6]quinolinic acid were produced by unstimulated cultures of microglia and macrophages. Interferon γ, an inducer of indoleamine 2,3-dioxygenase, increased the accumulation of l-kynurenine by all three cell types (to more than 40 µM). Whereas large quantities of [13C6]quinolinic acid were produced by microglia and macrophages (to 438 and 1410 nM respectively), minute quantities of [13C6]quinolinic acid were produced in human fetal brain cultures (not more than 2 nM). Activated microglia and macrophage infiltrates into the brain might be an important source of accelerated conversion of l-tryptophan into quinolinic acid within the central nervous system in inflammatory diseases.

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Lokhonina, Anastasia, Andrey Elchaninov, Timur Fatkhudinov, Andrey Makarov, Irina Arutyunyan, Maria Grinberg, Valeria Glinkina, et al. "Activated Macrophages of Monocytic Origin Predominantly Express Proinflammatory Cytokine Genes, Whereas Kupffer Cells Predominantly Express Anti-Inflammatory Cytokine Genes." BioMed Research International 2019 (March 5, 2019): 1–13. http://dx.doi.org/10.1155/2019/3912142.

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In the central nervous system and in the liver, the macrophage populations are represented exclusively by descendants of the hematopoietic progenitor cells of the yolk sac. The reasons for such differential distribution of macrophages are not fully understood. We found that, as can be judged by corresponding changes in the expression of CD86 and CD163 markers, the transient macrophages of monocytic lineage are more sensitive to activating stimuli. The two macrophage populations have distinct patterns of gene expression, which is particularly noticeable for M1- and M2-associated genes. For instance, Kupffer cells more readily develop and longer maintain the elevated expression levels of Il4, Il10, and Il13 upon the activation; by contrast, the macrophages of monocytic lineage express Il1b, Il12a, and Tnfα upon the activation. The obtained results allow us to conclude that the in vitro activated Kupffer cells of the liver are committed to M2 phenotype, whereas the in vitro activated monocyte-derived macrophages show a typical M1 behavior. These observations are likely to reflect the situation in the in vivo microenvironments.

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Kumar, Gaurav, Kaylea Massey, Rose M. Ko, and Robert C. Axtell. "BAFF and APRIL signaling through BCMA regulates microglial cells in the central nervous system." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 85.07. http://dx.doi.org/10.4049/jimmunol.210.supp.85.07.

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Abstract B cell Maturation Antigen (BCMA) is a receptor that engages the cytokines BAFF and APRIL. BCMA is known to play a critical role in regulating B cell proliferation, survival, and differentiation into plasma cells. However, the effect of BCMA on non-B cells has been understudied. We have previously shown that BCMA regulates EAE, where BCMA −/−mice have exacerbated disease compared to BCMA +/+mice. The increased disease in the BCMA −/−mice was associated with increased infiltration of B cells, T cells and inflammatory macrophages in the central nervous system (CNS). In this study, we assessed the expression patterns of BCMA on different immune cell types infiltrating the CNS of mice with EAE by flow cytometry. We found BCMA is expressed on plasma cells, microglia and inflammatory macrophages that are in the CNS, but not T cells or neutrophils. Next, we compared the numbers and phenotype of different myeloid cells in the CNS and lymph nodes in healthy BCMA −/−and BCMA +/+mice. We found that BCMA −/−mice have an increased number of resident microglial cells with low CD86 expression in the brain compared to BCMA +/+mice. Also, we found elevated numbers of macrophages with M1 (measured by the expression of iNOS) phenotype in the brain of BCMA −/−mice compared to BCMA +/+mice. In lymph nodes, we found an increased number of M1 type macrophages in the BCMA −/−in comparison to BCMA +/+mice with low CD86 expression. These data suggest a novel role for BCMA in regulating the phenotype and function of microglial and macrophages in CNS and in the peripheral immune tissues. Our data points towards a new pathway regulated by BAFF and APRIL signaling through BCMA and provides clues behind the immunopathogenesis of neuroautoimmune diseases. This study was supported by grants from the NMSS (RG-1602-07722), the NIH (R01AI137047 and R01EY027346) awarded to R.C. Axtell.

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Pages-Geli, Carlota, Daniel Medina, Cristina Hernandez, Patricia Fernandez, Gemma Pujadas, Francesc Bosch, and Marta Crespo. "Macrophages Play a Key Role in Controlling Tumor Growth and Response to Immunotherapy in Primary Central Nervous System Lymphoma." Blood 142, Supplement 1 (November 28, 2023): 1642. http://dx.doi.org/10.1182/blood-2023-180719.

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Introduction Primary Central Nervous System Lymphoma (PCNSL) represents 5% of extranodal lymphomas. Current treatments include high-dose chemotherapy in combination with an anti-CD20 antibody, and whole-brain radiation, both of which are limited by their toxicity. Although some advances have been achieved during the last few years, the prognosis of patients with CNS lymphoma is substantially worse than those with other type of lymphomas, with 5-year survival rates around 30%. The highly aggressive nature of CNS lymphomas is in part due to the fact that the brain is an immunoprivileged organ; it presents very low levels of immunosurveillance, which contributes to inefficient immune responses against malignant cells. Of note, up to 70% of patients diagnosed with PCNSL also exhibit genetic alterations to avoid recognition by the immune system, like loss of MHC-I, that prevent presentation of tumor antigens, and amplifications in PD-L1, which increase the negative stimuli in cytotoxic T cells. The PD-1/PD-L1 interaction has mainly been considered to be a checkpoint that regulates T cells. However, it has recently been found that tumor-associated macrophages can also express PD-1 and become activated to attack tumor cells when it is blocked. Moreover, macrophages have also been found to be inhibited by MHC-I expression on cancer cells. Thus, cancer cells that downregulate MHC-I to avoid T cell surveillance are particularly vulnerable to macrophages phagocytosis, especially when other macrophage immune checkpoints are blocked, such as CD47. Against this background, we aimed to decipher the differential role of macrophages and T cells in the tumor growth and response to immunotherapy in primary CNS lymphoma. Methods Luciferase-expressing A20 murine B-cell lymphoma cells were genetically modified to knock-out MHCI or MHCII by CRISPR-Cas9 and injected into the brain of immunocompetent (IC) or macrophage-depleted (MD) mice. Once tumours were stablished, mice were treated intravenously with seven injections, twice a week, of anti-PD1, anti-CD47 or the combination of both. We monitored mice for survival and tumoral growth. Additionally, brains were collected from mice treated with three injections for analysis of macrophages, B cells and T cells using flow cytometry and IHC. Results In IC mice, all anti-PD1 treated mice showed significant differences in tumoral growth and survival compared to vehicle; however, MHCI- tumors had the lowest overall survival (Figure 1A). With anti-CD47 therapy, only MHCI- PCNSL mice had a significantly increased survival compared to vehicle. Combination was effective in all groups, but no drug synergy was seen. In MD mice, all tumors were more aggressive than in IC mice. With anti-PD1, MHCI+ PCNSL mice achieved a complete tumor regression and survived longer in comparison to vehicle. On the contrary, MHCI- PCNSL mice didn't respond to anti-PD1 therapy (Figure 1B). Of notice, MHCI+ PCNSL in both MD and IC models had a higher infiltration of active T cells when treated with anti-PD1. In MHCI- PCNSL, infiltrated T cells had less expression of activation markers in both models and macrophages were polarized to an M2 phenotype in IC mice. Conclusions Our study revealed a remarkable response to anti-PD1 therapy in MHCI+ CNS lymphoma tumors, regardless of the presence of macrophages in the tumor microenvironment. This indicates that T cells would be primarily responsible for the observed tumour regression. However, targeting CD47 in MHCI+ PCNSL was found to be insufficient in restoring macrophage phagocytosis. Despite observing positive effects of anti-PD1 and anti-CD47 drugs in our MHCI- immunocompetent mouse model, MHCI downregulation still induces a very aggressive, lethal disease. This suggests that these tumors can only be controlled by macrophages, as supported by the lack of treatment response in a MD microenvironment. Our findings highlight the critical role of macrophages in controlling the growth of lymphoma cells in the brain and their significance in the immunotherapy response for CNS lymphomas, particularly when MHCI expression is deficient. Blocking PD1 exhibits superior efficacy when macrophages are present, indicating T cells are not the only player in this tumoral scenario. As a result, our study suggests that a promising approach for treating primary CNS lymphomas would involve targeting both T cells and macrophages.

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Fischer, Hans-Georg, and Gaby Reichmann. "Brain Dendritic Cells and Macrophages/Microglia in Central Nervous System Inflammation." Journal of Immunology 166, no. 4 (February 15, 2001): 2717–26. http://dx.doi.org/10.4049/jimmunol.166.4.2717.

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Takahashi, Kazuya, Yumiko Kakuda, Saori Munemoto, Hirohito Yamazaki, Ichiro Nozaki, and Masahito Yamada. "Long-lived human tissue-resident macrophages in the central nervous system." Clinical and Experimental Neuroimmunology 7, no. 3 (April 1, 2016): 286–87. http://dx.doi.org/10.1111/cen3.12301.

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Goldmann, Tobias, Peter Wieghofer, Marta Joana Costa Jordão, Fabiola Prutek, Nora Hagemeyer, Kathrin Frenzel, Lukas Amann, et al. "Origin, fate and dynamics of macrophages at central nervous system interfaces." Nature Immunology 17, no. 7 (May 2, 2016): 797–805. http://dx.doi.org/10.1038/ni.3423.

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Lane, Thomas E., Michael T. Liu, Benjamin P. Chen, Valérie C. Asensio, Roger M. Samawi, Alyssa D. Paoletti, Iain L. Campbell, Stephen L. Kunkel, Howard S. Fox, and Michael J. Buchmeier. "A Central Role for CD4+ T Cells and RANTES in Virus-Induced Central Nervous System Inflammation and Demyelination." Journal of Virology 74, no. 3 (February 1, 2000): 1415–24. http://dx.doi.org/10.1128/jvi.74.3.1415-1424.2000.

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ABSTRACT Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a demyelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyelinating disease multiple sclerosis. The contributions of CD4+ and CD8+ T cells in the pathogenesis of the disease were investigated. Significantly less severe inflammation and demyelination were observed in CD4−/− mice than in CD8−/− and C57BL/6 mice (P ≤ 0.002 andP ≤ 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4−/− mice had a significant reduction in numbers of activated macrophages/microglial cells in the brain compared to the numbers in CD8−/− and C57BL/6 mice, indicating a role for these cells in myelin destruction. Furthermore, CD4−/−mice displayed lower levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the pathogenesis of MHV-induced neurologic disease. Administration of RANTES antisera to MHV-infected C57BL/6 mice resulted in a significant reduction in macrophage infiltration and demyelination (P ≤ 0.001) compared to those in control mice. These data indicate that CD4+ T cells have a pivotal role in accelerating CNS inflammation and demyelination within infected mice, possibly by regulating RANTES expression, which in turn coordinates the trafficking of macrophages into the CNS, leading to myelin destruction.

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Lee, Heyne, William S. James, and Sally A. Cowley. "LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson's disease." Biochemical Society Transactions 45, no. 1 (February 8, 2017): 131–39. http://dx.doi.org/10.1042/bst20160262.

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are found in familial and idiopathic cases of Parkinson's disease (PD), but are also associated with immune-related disorders, notably Crohn's disease and leprosy. Although the physiological function of LRRK2 protein remains largely elusive, increasing evidence suggests that it plays a role in innate immunity, a process that also has been implicated in neurodegenerative diseases, including PD. Innate immunity involves macrophages and microglia, in which endogenous LRRK2 expression is precisely regulated and expression is strongly up-regulated upon cell activation. This brief report discusses the current understanding of the involvement of LRRK2 in innate immunity particularly in relation to PD, critically examining its role in myeloid cells, particularly macrophages and microglia.

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Koedel, Uwe, Frank Winkler, Barbara Angele, Adriano Fontana, and Hans-Walter Pfister. "Meningitis-Associated Central Nervous System Complications are Mediated by the Activation of Poly(ADP-ribose) Polymerase." Journal of Cerebral Blood Flow & Metabolism 22, no. 1 (January 2002): 39–49. http://dx.doi.org/10.1097/00004647-200201000-00005.

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The present study assessed the role of PARP [poly(adenosine diphosphate-ribose) polymerase] activation in experimental pneumococcal meningitis. Mice with a targeted disruption of the PARP1 gene were protected against meningitis-associated central nervous system complications including blood-brain barrier breaching and increase in intracranial pressure. This beneficial effect was paralleled by a significant reduction in meningeal inflammation, as evidenced by significantly lower cerebrospinal fluid leukocyte counts and interleukin-1β, −6, and tumor necrosis factor-α concentrations in the brain (compared with infected wild-type mice). The reduction in inflammation and central nervous system complications was associated with an improved clinical status of infected, PARP1-deficient mice. A similar protective effect was achieved by PARP inhibition using 3-aminobenzamide, the pharmacologic efficacy of which was confirmed by a marked attenuation of meningitis-induced poly(ADP)ribose formation. When the rat brain-derived endothelial cell line GP8.3 was cocultured with macrophages, exposure to pneumococci induced endothelial cell death and was paralleled by PARP activation and a reduction in the oxidized form of cellular nicotinamide adenine dinucleotide content. Treatment with 3-aminobenzamide significantly attenuated cellular nicotinamide adenine dinucleotide depletion and pneumococci-induced cytotoxicity. Thus, PARP activation seems to play a crucial role in the development of meningitis-associated central nervous system complications and pneumococci-induced endothelial injury. Inhibitors of PARP activation could provide a potential therapy of acute bacterial meningitis.

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Loeb, Anisha M., Siobhan S. Pattwell, Antonio Bedalov, Soheil Meshinchi, and Keith R. Loeb. "Donor Bone Marrow Derived Macrophage Engraftment into the Central Nervous System of Allogeneic Transplant Patients." Blood 138, Supplement 1 (November 5, 2021): 645. http://dx.doi.org/10.1182/blood-2021-148203.

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Abstract Introduction: Hematopoietic stem cell transplantation (HSCT) has had a major impact on the treatment of hematologic malignancies. Recent studies have shown the role HSCT can have in gene therapy by providing long-lived genetically modified cells to treat a variety of human diseases. It is well known that HSC and bone marrow-derived cells can differentiate into long-lived tissue macrophages and populate a wide spectrum of tissues including the brain. These cells are termed bone marrow derived macrophages and are akin to microglial cells in both morphology and function. There is an expanding literature of preclinical animal studies focused on the potential benefits of bone marrow derived-macrophage engraftment into the central nervous system (CNS). In this study we report the detection and characterization of donor bone marrow-derived macrophages in the cerebral cortex of allogeneic transplant patients. Methods: To determine the frequency of donor cell engraftment in post-transplant patients, we selected a cohort of 20 patients who had undergone a sex-mismatched transplant. Formalin fixed paraffin embedded cerebral cortex samples were obtained from the Fred Hutch tissue repository. Samples from male and female autologous transplants were used as controls. Tissue sections were stained by XY fluorescent in situ hybridization (FISH) to identify male and female cells. The XY FISH-stained slides were imaged at 40X magnification on a TissueFAX system. Scanned images were analyzed in blinded fashion using TissueQuest software. Male donor cells were defined by the presence of the Y chromosome within DAPI stained nuclei. Parameters were established using a small area and then applied to a larger area covering 10,000-15,000 cells. Identified donors were confirmed by manual inspection. Adjacent sections were used in Iba1 immunohistochemistry (IHC) studies to quantify the microglia/macrophage population. Select cases were used in double fluorescent Iba1 IHC (tyramide signal amplification)/XY-FISH studies to identify the donor cell type. Results: Intraparenchymal donor bone marrow derived cells were identified in all cerebral cortex sex mismatched samples. To determine the identity of donor cells, select cases were stained with fluorescent tyramide based Iba1 IHC, imaged, stained with XY FISH and re-imaged. The majority of donor cells (>80%) showed strong expression of Iba1, confirming them to be bone marrow-derived macrophages. In parallel Iba1 IHC studies we showed that microglial cells constitute ~12% of the scanned cell population. Thus, when computed as a percentage of the macrophage/microglial population, donor cells from myeloablative transplants range from 4.2-25%. The bone marrow derived cells are stable over time since length of the post-transplant period did not have a major impact on the number of donor cells. Prior animal studies have demonstrated the importance of conditioning (total body irradiation (TBI) or Busulfan) in providing access to the CNS and stimulating engraftment. Consistently, we found that the strength of the conditioning regimen had a significant impact on donor cell engraftment into the CNS. Donor cells in myeloablative cases (>1,000cGy) averaged 8.0% (4.2-14.9%) of microglial cells, while those in non-myeloablative cases (<300cGy) averaged 1.3% (1.2-1.3%). In agreement with preclinical studies, we also noted that myeloablative cases from Busulfan or Treosulfan based conditioning had similar levels of donor-derived cells as cases with TBI myeloablative conditioning, averaging 6.6% (4.4-8.3%) of microglial cells. Although only a limited number of samples were available for analysis, the highest level of donor engraftment was observed in patients who had received 2 separate transplants; on average they comprised 16.3% (12.2-25.1%) of microglial cells. Conclusion: This, the largest study of bone marrow-derived macrophages in post-transplant patients, shows that donor derived cells from myeloablative transplants account for 4.1-25.1% of microglial cells. Donor engraftment is highest following myeloablative conditioning or in patients receiving multiple transplants, and lowest in non-myeloablative cases. Our studies document the magnitude of donor-derived macrophages in the CNS following a bone marrow transplant and serve as a basis for future gene therapy studies targeting neurodegenerative disorders. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Richard, Seidu A. "The Pivotal Immunoregulatory Functions of Microglia and Macrophages in Glioma Pathogenesis and Therapy." Journal of Oncology 2022 (April 4, 2022): 1–19. http://dx.doi.org/10.1155/2022/8903482.

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Gliomas are mixed solid tumors composed of both neoplastic and nonneoplastic cells. In glioma microenvironment, the most common nonneoplastic and infiltrating cells are macrophages and microglia. Microglia are the exact phagocytes of the central nervous system, whereas macrophages are myeloid immune cells that are depicted with ardent phagocytosis. Microglia are heterogeneously located in almost all nonoverlapping sections of the brain as well as the spinal cord, while macrophages are derived from circulating monocytes. Microglia and macrophages utilize a variety of receptors for the detection of molecules, particles, and cells that they engulf. Both microglia and peripheral macrophages interact directly with vessels both in the periphery of and within the tumor. In glioma milieu, normal human astrocytes, glioma cells, and microglia all exhibited the ability of phagocytosing glioma cells and precisely apoptotic tumor cells. Also, microglia and macrophages are robustly triggered by the glioma via the expression of chemoattractants such as monocyte chemoattractant protein, stromal-derived factor-1, and macrophage-colony stimulating factor. Glioma-associated microglia and/or macrophages positively correlated with glioma invasiveness, immunosuppression, and patients’ poor outcome, making these cells a suitable target for immunotherapeutic schemes.

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Rock, R. Bryan, Genya Gekker, Shuxian Hu, Wen S. Sheng, Maxim Cheeran, James R. Lokensgard, and Phillip K. Peterson. "Role of Microglia in Central Nervous System Infections." Clinical Microbiology Reviews 17, no. 4 (October 2004): 942–64. http://dx.doi.org/10.1128/cmr.17.4.942-964.2004.

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SUMMARY The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed.

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Tran, Elise H., Karin Hoekstra, Nico van Rooijen, Christine D. Dijkstra, and Trevor Owens. "Immune Invasion of the Central Nervous System Parenchyma and Experimental Allergic Encephalomyelitis, But Not Leukocyte Extravasation from Blood, Are Prevented in Macrophage-Depleted Mice." Journal of Immunology 161, no. 7 (October 1, 1998): 3767–75. http://dx.doi.org/10.4049/jimmunol.161.7.3767.

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Abstract Organ-specific autoimmune diseases are characterized by infiltrates, including T lymphocytes and activated macrophages. Macrophages and secondarily activated tissue resident counterparts can both present Ag to and contribute to cytokine secretion by T lymphocytes. We have previously shown a crucial role of peripheral macrophages in experimental allergic encephalomyelitis (EAE), a Th1-mediated demyelinating disease that serves as a an animal model for multiple sclerosis (MS), by their depletion using mannosylated liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP). Here we describe studies to investigate the mechanisms by which macrophages contribute to the lesion formation in EAE, by studying the effect of Cl2MDP-containing mannosylated liposomes (Cl2MDP-mnL) on adoptively transferred EAE in SJL/J mice. Adoptive transfer of EAE with myelin basic protein-reactive CD4+ T cells to SJL/J mice was abrogated by Cl2MDP-mnL treatment. CD4+ T cell and MHC II+ B220+ B cell extravasation from blood vessels and Th1 cytokine production were not inhibited. However, invasion of the central nervous system intraparenchymal tissues by lymphocytes, F4/80+, Mac-1+, and MOMA-1+ macrophages was almost completely blocked after treatment with Cl2MDP-mnL. Furthermore, in Cl2MDP-mnL-treated mice, the myelin sheaths appeared completely normal, whereas, in the control groups, marked demyelination occurred. Production of TNF-α and inducible nitric oxide synthase, both associated with macrophage/microglial activation, was inhibited. This intervention reveals a role for macrophages in regulating the invasion of autoreactive T cells and secondary glial recruitment that ordinarily lead to demyelinating pathology in EAE and multiple sclerosis.

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Kobayakawa, Kazu, Yasuyuki Ohkawa, Shingo Yoshizaki, Tetsuya Tamaru, Takeyuki Saito, Ken Kijima, Kazuya Yokota, et al. "Macrophage centripetal migration drives spontaneous healing process after spinal cord injury." Science Advances 5, no. 5 (May 2019): eaav5086. http://dx.doi.org/10.1126/sciadv.aav5086.

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Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.

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Shastri, Abhishek, Domenico Marco Bonifati, and Uday Kishore. "Innate Immunity and Neuroinflammation." Mediators of Inflammation 2013 (2013): 1–19. http://dx.doi.org/10.1155/2013/342931.

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Inflammation of central nervous system (CNS) is usually associated with trauma and infection. Neuroinflammation occurs in close relation to trauma, infection, and neurodegenerative diseases. Low-level neuroinflammation is considered to have beneficial effects whereas chronic neuroinflammation can be harmful. Innate immune system consisting of pattern-recognition receptors, macrophages, and complement system plays a key role in CNS homeostasis following injury and infection. Here, we discuss how innate immune components can also contribute to neuroinflammation and neurodegeneration.

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Williams, Kenneth C., and William F. Hickey. "Central Nervous System Damage, Monocytes and Macrophages, and Neurological Disorders in AIDS." Annual Review of Neuroscience 25, no. 1 (March 2002): 537–62. http://dx.doi.org/10.1146/annurev.neuro.25.112701.142822.

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44

Rawji, Khalil S., Manoj K. Mishra, Nathan J. Michaels, Serge Rivest, Peter K. Stys, and V. Wee Yong. "Immunosenescence of microglia and macrophages: impact on the ageing central nervous system." Brain 139, no. 3 (January 29, 2016): 653–61. http://dx.doi.org/10.1093/brain/awv395.

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45

Stefansson, Kari, Anthony T. Reder, and Jack P. Antel. "An epitope shared by central nervous system myelin and peripheral blood macrophages." Journal of Neuroimmunology 12, no. 1 (July 1986): 49–55. http://dx.doi.org/10.1016/0165-5728(86)90096-2.

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46

Taketomi, Takumi, and Fuminori Tsuruta. "Towards an Understanding of Microglia and Border-Associated Macrophages." Biology 12, no. 8 (August 5, 2023): 1091. http://dx.doi.org/10.3390/biology12081091.

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The central nervous system (CNS) plays a crucial role in regulating bodily functions by sensing and integrating environmental cues and maintaining proper physiological conditions. Recent research has revealed that CNS functions are closely coordinated with the immune system. As even minor disturbances of the immune system in the CNS can lead to various dysfunctions, diseases, or even death, it is highly specialized and segregated from that in peripheral regions. Microglia in the parenchyma and macrophages at the interface between the CNS and peripheral regions are essential immune cells in the CNS that monitor environmental changes. Recent omics analyses have revealed that these cells exhibit highly heterogeneous populations. In this review, we summarize the functions and diversity of microglia in the brain parenchyma and those of macrophages in the border regions, such as the meninges, perivascular spaces, and choroid plexus.

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47

Liu, Min, Liang Hong, Shruti Sridhar, Patrick Jaynes, Chartsiam Tipgomut, Limei Poon, Sanjay De Mel, et al. "Spatial-Resolved Transcriptomics Reveals Immune Landscape Variations in Primary Central Nervous System Lymphoma (PCNSL) and Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 144, Supplement 1 (November 5, 2024): 3004. https://doi.org/10.1182/blood-2024-209497.

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Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma with a high risk of recurrence, posing significant clinical challenges due to its morbidity. While PD1-based immunotherapy has shown promise in some PCNSL cases, it has been less effective in diffuse large B-cell lymphoma (DLBCL). Understanding the tumor microenvironment factors that distinguish PCNSL from DLBCL and those mediating PCNSL relapse after standard chemotherapy is crucial for integrating immunotherapy into treatment. In this study, we employed digital spatial profiling (DSP), an advanced technique for spatially resolved transcriptomics, to capture the whole transcriptome atlas (WTA) with over 18,000 RNA targets across specific cell types. Using DSP, we profiled the WTA of macrophages, T cells, and B cells in tumor tissue samples from patients with DLBCL (n = 64) and PCNSL (n = 16), encompassing 409 areas of interest (AOIs). Selective collection of UV-cleavable probes from distinct masks, generated by immunofluorescent staining of the morphology markers CD68, CD3, and CD20, accurately captured the WTA of respective cell types in their native tissue environment. We identified many differentially expressed genes (DEGs) significantly upregulated in DLBCL or PCNSL (adjusted P value < 0.05 and |log2FC| > 0.58). In PCNSL tumor cells, immune checkpoints such as LAG-3 and chemokines (CXCL13, CCL3, CCL5) were actively upregulated. Pathway enrichment analysis revealed that inflammatory response, complement, and IL-2/STAT5 signaling were enriched in PCNSL tumor cells, indicating a more pronounced immune response within the tumor microenvironment, potentially contributing to the preferential sensitivity to PD1 therapy. Significant differences were also noted in the macrophage compartment between DLBCL and PCNSL. DEGs such as SPP1 and CD163 were highly expressed in PCNSL macrophages. Metabolic pathways such as hypoxia and glycolysis were enriched in PCNSL macrophages, suggesting that metabolic reprogramming may create a pro-tumorigenic microenvironment that supports tumor progression. Utilizing MoMac-VERSE, the largest single-cell transcriptomic meta-analysis of human monocytes and macrophages, we projected the top DEGs of the CD68 mask and found that PCNSL macrophage DEGs overlapped with the TREM2 macrophage cluster. This cluster has been shown to be associated with a poor prognosis and attenuate responses to PD-1 antibodies in various solid cancers, indicating that this specific macrophage subpopulation in PCNSL may have unique functions in shaping the tumor microenvironment and affecting the response to immune checkpoint inhibitors. In summary, leveraging DSP, we present a comprehensive understanding of the distinct immune landscapes in DLBCL and PCNSL. Our findings highlight the importance of spatial transcriptomics in elucidating the unique characteristics of these lymphoma subtypes and may have implications for novel immunotherapeutic treatment strategies.

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48

Berman, J. W., M. P. Guida, J. Warren, J. Amat, and C. F. Brosnan. "Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat." Journal of Immunology 156, no. 8 (April 15, 1996): 3017–23. http://dx.doi.org/10.4049/jimmunol.156.8.3017.

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Abstract Monocyte chemoattractant protein-1 (MCP-1) is a member of the chemokine beta family of chemoattractants that has been shown to play a major role in the initiation of monocyte and T cell inflammation to sites of tissue injury. In this study, we have examined the distribution of MCP-1 expression in inflammation in the central nervous system (CNS) associated with the autoimmune disease experimental autoimmune encephalomyelitis (EAE) and compared the results with those detected in inflammation associated with trauma. In EAE, MCP-1 expression was detected at the onset of inflammation, prior to clinical expression of disease, in lymphocytes and endothelial cells in subarachnoid locations. Monocyte infiltration into these areas appeared 24 h later. After the onset of clinical signs, MCP-1 expression was widely distributed in the spinal cord with levels increasing and decreasing in association with disease activity. Lymphocytes, macrophages, astrocytes, and endothelial cells could be identified as sources of MCP-1 by immunoreactivity and in situ hybridization. A similar close correlation between macrophage infiltration and the levels of mRNA for MCP-1 was found in the CNS of rats subjected to trauma, and in these animals MCP-1 was detected by immunohistochemistry in macrophages and endothelial cells. The results support the conclusion that MCP-1 is an important mediator of inflammation in the CNS.

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Cary, Daniele, Janice Clements, and Andrew Henderson. "RON Receptor Tyrosine Kinase, a Negative Regulator of Inflammation, is Decreased During SIV Associated Central Nervous System Disease. (168.33)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 168.33. http://dx.doi.org/10.4049/jimmunol.188.supp.168.33.

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Abstract Expressed on tissue resident macrophages, the receptor tyrosine kinase, RON, functions to maintain inflammation homeostatisis by activating genes that promote wound repair and resolve inflammation; while repressing genes that perpetuate tissue damage. Chronic HIV infection is associated with dysregulated inflammation that contributes to organ diseases, and we hypothesize that altered RON expression contributes to the development of HIV associated CNS disease. We developed a tractable in vitro model using macrophages isolated from human tonsil; these cells express CD14, CD16, CD206, CCR5, and RON. Treatment with RON ligand induced arginase and inhibited HIV and IL-12p40. Following infection, RON expression was down-regulated. We utilized a well characterized SIV model in macaques to explore the temporal regulation of RON in the brain. Following prolonged SIV infection, RON expression decreased. RON was maintained in animals that did not develop CNS disease and was reduced in macaques that demonstrated CNS disease symptoms. Arginase expression was reduced during late infection whereas expression of the inflammatory genes, interleukin 12p40 and TNFα was elevated. Our data support a model in which during acute SIV infection in the brain, active inflammation is controlled by RON, however, following prolonged infection, RON expression is decreased, genes that quell inflammation are repressed, and inflammatory mediators are induced to directly promote CNS disease.

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Assi, Emma, Denise Cazzato, Clara De Palma, Cristiana Perrotta, Emilio Clementi, and Davide Cervia. "Sphingolipids and Brain Resident Macrophages in Neuroinflammation: An Emerging Aspect of Nervous System Pathology." Clinical and Developmental Immunology 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/309302.

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Sphingolipid metabolism is deeply regulated along the differentiation and development of the central nervous system (CNS), and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system. Microglia are resident macrophages of the CNS involved in general maintenance of neural environment. Modulations in microglia phenotypes may contribute to pathogenic forms of inflammation. Since defects in macrophage/microglia activity contribute to neurodegenerative diseases, it will be essential to systematically identify the components of the microglial cell response that contribute to disease progression. In such complex processes, the sphingolipid systems have recently emerged to play important roles, thus appearing as a key new player in CNS disorders. This review provides a rationale for harnessing the sphingolipid metabolic pathway as a potential target against neuroinflammation.

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