Key Points
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Much of the development and physiology of the central nervous system (CNS) is governed through cytokine networks, which when deregulated contribute to tissue inflammation.
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CNS inflammation does not require tissue-invasion by blood-borne cells, but can occur as a result of a local tissue response to abnormal changes in the microenvironment.
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In degenerative diseases such as proteopathies (for example, Alzheimer disease), CNS-resident cells are the predominant producers of pro-inflammatory cytokines.
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In classical neuroinflammatory diseases, such as multiple sclerosis and encephalitides, pro-inflammatory cytokines are the major payload delivered by tissue-invading leukocytes.
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In proteopathies and neurodegeneration, the initial tissue response to disturbances in normal homeostasis is primarily beneficial, that is, intended to counteract or repair the imbalance. On the other hand, chronic over-production of cytokines over long periods of time can also render CNS-resident cells dystrophic or even irreversibly 'exhausted', which in turn fuels the degenerative processes.
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In inflammatory demyelination or encephalitides, tissue invasion by leukocytes is detrimental and cytokines delivered to the CNS fuel the inflammatory cascade and lead to tissue damage.
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CNS tissue damage is in all likelihood mediated by tissue-invading myeloid cells and not by lymphocytes. Our understanding of the myeloid response to inflammation and deregulated cytokine networks is still in its infancy.
Abstract
Cytokines provide cells with the ability to communicate with one another and orchestrate complex multicellular behaviour. There is an emerging understanding of the role that cytokines play in normal homeostatic tissue function and how dysregulation of these cytokine networks is associated with pathological conditions. The central nervous system (CNS), where few blood-borne immune cells circulate, seems to be particularly vulnerable to dysregulated cytokine networks. In degenerative diseases, such as proteopathies, CNS-resident cells are the predominant producers of pro-inflammatory cytokines. By contrast, in classical neuroinflammatory diseases, such as multiple sclerosis and encephalitides, pro-inflammatory cytokines are mainly produced by tissue-invading leukocytes. Whereas the effect of dysregulated cytokine networks in proteopathies is controversial, cytokines delivered to the CNS by invading immune cells are in general detrimental to the tissue. Here, we summarize recent observations on the impact of dysregulated cytokine networks in neuroinflammation.
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References
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context ofan inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 24, 179–189 (2006).
Korn, T. et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc. Natl Acad. Sci. USA 105, 18460–18465 (2008).
Goverman, J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9, 393–407 (2009).
Ransohoff, R. M., Kivisakk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3, 569–581 (2003).
Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).
Deverman, B. E. & Patterson, P. H. Cytokines and CNS development. Neuron 64, 61–78 (2009).
Hatta, T., Moriyama, K., Nakashima, K., Taga, T. & Otani, H. The Role of gp130 in cerebral cortical development: in vivo functional analysis in a mouse ex utero system. J. Neurosci. 22, 5516–5524 (2002). This paper reveals the role for cytokine receptor signalling, in particular gp130, in mammalian brain development.
Boulanger, L. M. Immune proteins in brain development and synaptic plasticity. Neuron 64, 93–109 (2009).
Adachi, T., Takanaga, H., Kunimoto, M. & Asou, H. Influence of LIF and BMP-2 on differentiation and development of glial cells in primary cultures of embryonic rat cerebral hemisphere. J. Neurosci. Res. 79, 608–615 (2005).
Barnabe-Heider, F. et al. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 48, 253–265 (2005).
Gregg, C. & Weiss, S. CNTF/LIF/gp130 receptor complex signaling maintains a VZ precursor differentiation gradient in the developing ventral forebrain. Development 132, 565–578 (2005).
Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).
Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012). References 12 and 13 appeared in the same year and described the role of IL-34 in microglia maintenance. They differ, however, in their interpretation of the impact of IL-34 on embryonic microglia development.
Mizuno, T. et al. Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity. Am. J. Pathol. 179, 2016–2027 (2011).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This is a seminal study solidifying that microglia are not bone marrow-derived cells, but instead stem from yolk sac macrophages early during development and are not replenished.
Jin, S. et al. Interleukin-34 restores blood-brain barrier integrity by upregulating tight junction proteins in endothelial cells. PLoS ONE 9, e115981 (2014).
Streit, W. J. & Graeber, M. B. Heterogeneity of microglial and perivascular cell populations: insights gained from the facial nucleus paradigm. Glia 7, 68–74 (1993).
Chamorro, A. et al. The immunology of acute stroke. Nat. Rev. Neurol. 8, 401–410 (2012).
Waisman, A., Liblau, R. S. & Becher, B. Innate and adaptive immune responses in the CNS. Lancet Neurol. 14, 945–955 (2015).
Walsh, J. G., Muruve, D. A. & Power, C. Inflammasomes in the CNS. Nat. Rev. Neurosci. 15, 84–97 (2014).
Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
Crehan, H., Hardy, J. & Pocock, J. Microglia, Alzheimer's disease, and complement. Int. J. Alzheimers Dis. 2012, 983640 (2012).
Moore, K. J. et al. A CD36-initiated signaling cascade mediates inflammatory effects of β-amyloid. J. Biol. Chem. 277, 47373–47379 (2002).
Lue, L. F. et al. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Exp. Neurol. 171, 29–45 (2001).
Hu, W. T. et al. Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 79, 897–905 (2012).
Griffin, W. S. et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA 86, 7611–7615 (1989).
Patel, N. S. et al. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease. J. Neuroinflamm. 2, 9 (2005).
Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J. & Kipnis, J. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 85, 703–709 (2015). This paper demonstrates that cytokines stored in CNS-resident cells can act as alarmins and trigger reparative immune responses.
Schwartz, M., Kipnis, J., Rivest, S. & Prat, A. How do immune cells support and shape the brain in health, disease, and aging? J. Neurosci. 33, 17587–17596 (2013).
Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).
Chakrabarty, P. et al. Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 24, 548–559 (2010).
Chakrabarty, P., Herring, A., Ceballos-Diaz, C., Das, P. & Golde, T. E. Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo. Mol. Neurodegener. 6, 16 (2011).
Fillit, H. et al. Elevated circulating tumor necrosis factor levels in Alzheimer's disease. Neurosci. Lett. 129, 318–320 (1991).
Cheng, X., Yang, L., He, P., Li, R. & Shen, Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer's disease and non-demented patients. J. Alzheimers Dis. 19, 621–630 (2010).
Butchart, J. et al. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 84, 2161–2168 (2015). A clinical trial of neutralizing TNF in Alzheimer disease.
Ghosh, S. et al. Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J. Neurosci. 33, 5053–5064 (2013).
Shaftel, S. S. et al. Chronic interleukin-1β expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J. Neurosci. 27, 9301–9309 (2007).
Kitazawa, M. et al. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer's disease model. J. Immunol. 187, 6539–6549 (2011).
He, P. et al. Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer's mice. J. Cell Biol. 178, 829–841 (2007).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013). Demonstration of inflammasome activation in a mouse model of Alzheimer disease.
Vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nat. Med. 18, 1812–1819 (2012).
Ribizzi, G., Fiordoro, S., Barocci, S., Ferrari, E. & Megna, M. Cytokine polymorphisms and Alzheimer disease: possible associations. Neurol. Sci. 31, 321–325 (2010).
Papassotiropoulos, A. et al. A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease. Ann. Neurol. 45, 666–668 (1999).
Yu, J. T. et al. Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer's disease. Brain Res. 1253, 169–175 (2009).
Nicoll, J. A. et al. Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann. Neurol. 47, 365–368 (2000).
Ben-Nun, A., Wekerle, H. & Cohen, I. R. Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein. Nature 292, 60–61 (1981).
The International Multiple Sclerosis Genetics Consortium & The Welcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).
Kothur, K., Wienholt, L., Brilot, F. & Dale, R. C. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: a systematic review. Cytokine 77, 227–237 (2016).
Gutcher, I. & Becher, B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J. Clin. Invest. 117, 1119–1127 (2007).
Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 13, 715–725 (2000).
Segal, B. M. & Shevach, E. M. IL-12 unmasks latent autoimmune disease in resistant mice. J. Exp. Med. 184, 771–775 (1996).
Becher, B., Durell, B. G. & Noelle, R. J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Investig. 110, 493–497 (2002). This is the first report showing that IL-23 and not IL-12 is required for the pathogenesis of EAE.
Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003). Formal demonstration that the IL-23p19 subunit is mandatory for EAE development.
Li, Y. et al. Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain 130, 490–501 (2007).
Eugster, H. P., Frei, K., Kopf, M., Lassmann, H. & Fontana, A. IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur. J. Immunol. 28, 2178–2187 (1998).
Sonderegger, I. et al. GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J. Exp. Med. 205, 2281–2294 (2008).
Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009).
Vahedi, G., Kanno, Y., Sartorelli, V. & O'Shea, J. J. Transcription factors and CD4 T cells seeking identity: masters, minions, setters and spikers. Immunology 139, 294–298 (2013).
Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).
Pepper, M. et al. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat. Immunol. 11, 83–89 (2010). This report demonstrates that T H 17 cell polarization is short-lived and that T H 17 cells do not form memory populations.
Gagliani, N. et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015).
Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005). This paper shows that IL-23 induces a T H cell polarization distinct from T H 1 cells and that IL-23 induces expression of Il17a , among other genes.
Kreymborg, K. et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol. 179, 8098–8104 (2007).
Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560–567 (2011). This report shows that T cells must produce GM-CSF to be encephalitogenic.
Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22-IL-22R1 system. Nat. Rev. Drug Discov. 13, 21–38 (2014).
Miossec, P. & Kolls, J. K. Targeting IL-17 and TH17 cells in chronic inflammation. Nat. Rev. Drug Discov. 11, 763–776 (2012).
Perriard, G. et al. Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes. J. Neuroinflamm. 12, 119 (2015).
Das Sarma, J. et al. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J. Neuroinflamm. 6, 14 (2009).
Becher, B. & Segal, B. M. TH17 cytokines in autoimmune neuro-inflammation. Curr. Opin. Immunol. 23, 707–712 (2011).
Waisman, A., Hauptmann, J. & Regen, T. The role of IL-17 in CNS diseases. Acta Neuropathol. 129, 625–637 (2015).
Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).
Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).
Kebir, H. et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med. 13, 1173–1175 (2007).
Huppert, J. et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J. 24, 1023–1034 (2010).
Simmons, S. B., Liggitt, D. & Goverman, J. M. Cytokine-regulated neutrophil recruitment is required for brain but not spinal cord inflammation during experimental autoimmune encephalomyelitis. J. Immunol. 193, 555–563 (2014). This report shows that neutrophils are differentially required to mediate tissue damage in the brain but not in the spinal cord, highlighting the difference in response to inflammatory cells in these CNS microenvironments.
Kang, Z. et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32, 414–425 (2010).
Renauld, J. C. Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators. Nat. Rev. Immunol. 3, 667–676 (2003).
Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).
Duarte, J. H., Di Meglio, P., Hirota, K., Ahlfors, H. & Stockinger, B. Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo. PLoS ONE 8, e79819 (2013).
Panitch, H. S., Hirsch, R. L., Schindler, J. & Johnson, K. P. Treatment of multiple sclerosis with γ interferon: exacerbations associated with activation of the immune system. Neurology 37, 1097–1102 (1987). An early multiple sclerosis trial showing that treatment with IFN γ exacerbates disease.
Ottum, P. A., Arellano, G., Reyes, L. I., Iruretagoyena, M. & Naves, R. Opposing roles of interferon-γ on cells of the central nervous system in autoimmune neuroinflammation. Front. Immunol. 6, 539 (2015).
Simmons, R. D. & Willenborg, D. O. Direct injection of cytokines into the spinal-cord causes autoimmune encephalomyelitis-like inflammation. J. Neurol. Sci. 100, 37–42 (1990).
Sethna, M. P. & Lampson, L. A. Immune modulation within the brain – recruitment of inflammatory cells and increased major histocompatibility antigen expression following intracerebral injection of interferon-γ. J. Neuroimmunol. 34, 121–132 (1991).
Billiau, A. et al. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-γ. J. Immunol. 140, 1506–1510 (1988).
Steinman, L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13, 139–145 (2007).
Naves, R. et al. The interdependent, overlapping, and differential roles of type I and II IFNs in the pathogenesis of experimental autoimmune encephalomyelitis. J. Immunol. 191, 2967–2977 (2013).
Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Wang, Z. et al. Role of IFN-γ in induction of Foxp3 and conversion of CD4+ CD25- T cells to CD4+ Tregs. J. Clin. Invest. 116, 2434–2441 (2006).
Chin, Y. E., Kitagawa, M., Kuida, K., Flavell, R. A. & Fu, X. Y. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol. Cell. Biol. 17, 5328–5337 (1997).
Kwidzinski, E. et al. Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J. 19, 1347–1349 (2005).
Lin, W. et al. The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage. J. Clin. Invest. 117, 448–456 (2007).
Ding, X. et al. Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity. J. Immunol. 194, 4251–4264 (2015).
Hindinger, C. et al. IFN-γ signaling to astrocytes protects from autoimmune mediated neurological disability. PLoS ONE 7, e42088 (2012).
Ni, C. et al. Interferon-γ safeguards blood-brain barrier during experimental autoimmune encephalomyelitis. Am. J. Pathol. 184, 3308–3320 (2014).
Sosa, R. A., Murphey, C., Robinson, R. R. & Forsthuber, T. G. IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation. Proc. Natl Acad. Sci. USA 112, E5038–E5047 (2015).
Wensky, A. K. et al. IFN-γ determines distinct clinical outcomes in autoimmune encephalomyelitis. J. Immunol. 174, 1416–1423 (2005).
Lees, J. R., Golumbek, P. T., Sim, J., Dorsey, D. & Russell, J. H. Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis. J. Exp. Med. 205, 2633–2642 (2008).
Kroenke, M. A., Chensue, S. W. & Segal, B. M. EAE mediated by a non-IFN-γ/non-IL-17 pathway. Eur. J. Immunol. 40, 2340–2348 (2010).
Baruch, K. et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat. Med. 22, 135–137 (2016).
Browne, T. C. et al. IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J. Immunol. 190, 2241–2251 (2013).
Beck, J. et al. Increased production of interferon γ and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol. Scand. 78, 318–323 (1988).
Rieckmann, P. et al. Tumor necrosis factor-α messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann. Neurol. 37, 82–88 (1995).
Hovelmeyer, N. et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. J. Immunol. 175, 5875–5884 (2005).
Korn, T., Magnus, T. & Jung, S. Autoantigen specific T cells inhibit glutamate uptake in astrocytes by decreasing expression of astrocytic glutamate transporter GLAST: a mechanism mediated by tumor necrosis factor-α. FASEB J. 19, 1878–1880 (2005).
Rosenman, S. J., Shrikant, P., Dubb, L., Benveniste, E. N. & Ransohoff, R. M. Cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and astrocytoma cell lines. J. Immunol. 154, 1888–1899 (1995).
Benveniste, E. N., Sparacio, S. M. & Bethea, J. R. Tumor necrosis factor-alpha enhances interferon-γ-mediated class II antigen expression on astrocytes. J. Neuroimmunol. 25, 209–219 (1989).
Agresti, C. et al. Synergistic stimulation of MHC class I and IRF-1 gene expression by IFN-γ and TNF-α in oligodendrocytes. Eur. J. Neurosci. 10, 2975–2983 (1998).
The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53, 457–465 (1999). This report of a clinical trial shows that TNF-blockade exacerbates multiple sclerosis.
Mohan, N. et al. Demyelination occurring during anti-tumor necrosis factor α therapy for inflammatory arthritides. Arthritis Rheum. 44, 2862–2869 (2001).
Eugster, H. P. et al. Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur. J. Immunol. 29, 626–632 (1999).
Suvannavejh, G. C. et al. Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenesis of MOG(35–55)-induced experimental autoimmune encephalomyelitis. Cell. Immunol. 205, 24–33 (2000).
Nathan, C. & Cunningham-Bussel, A. Beyond oxidative stress: an immunologist's guide to reactive oxygen species. Nat. Rev. Immunol. 13, 349–361 (2013).
Naegele, M. et al. Neutrophils in multiple sclerosis are characterized by a primed phenotype. J. Neuroimmunol. 242, 60–71 (2012).
Rumble, J. M. et al. Neutrophil-related factors as biomarkers in EAE and MS. J. Exp. Med. 212, 23–35 (2015). This report suggests a role of CNS-invading neutrophils in neuroinflammation.
Pierson, E. R., Wagner, C. A. & Goverman, J. M. The contribution of neutrophils to CNS autoimmunity. Clin. Immunol. doi:10.1016/j.clim.2016.06.017 (2016).
McQualter, J. L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–882 (2001). The first paper showing that mice lacking GM-CSF are resistant to the development of EAE.
El-Behi, M. et al. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat. Immunol. 12, 568–575 (2011).
Croxford, A. L., Spath, S. & Becher, B. GM-CSF in neuroinflammation: licensing myeloid cells for tissue damage. Trends Immunol. 36, 651–662 (2015).
Reynolds, B. C. et al. Exposure to inflammatory cytokines selectively limits GM-CSF production by induced T regulatory cells. Eur. J. Immunol. 44, 3342–3352 (2014).
Croxford, A. L. et al. The cytokine GM-CSF drives the inflammatory signature of CCR2(+) monocytes and licenses autoimmunity. Immunity 43, 502–514 (2015). This paper shows that GM-CSF-produced by encephalitogenic T cells targets monocytes to develop into pathogenic-tissue invading phagocytes.
Huang, D. R., Wang, J., Kivisakk, P., Rollins, B. J. & Ransohoff, R. M. Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J. Exp. Med. 193, 713–726 (2001).
Mildner, A. et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009). This report shows that monocytes are crucial for the development of EAE.
Izikson, L., Klein, R. S., Charo, I. F., Weiner, H. L. & Luster, A. D. Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J. Exp. Med. 192, 1075–1080 (2000).
Fife, B. T., Huffnagle, G. B., Kuziel, W. A. & Karpus, W. J. CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J. Exp. Med. 192, 899–905 (2000).
Gaupp, S., Pitt, D., Kuziel, W. A., Cannella, B. & Raine, C. S. Experimental autoimmune encephalomyelitis (EAE) in CCR2(−/−) mice: susceptibility in multiple strains. Am. J. Pathol. 162, 139–150 (2003).
Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).
Vogel, D. Y. et al. Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J. Neuroinflamm. 10, 35 (2013).
Heneka, M. T. et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 14, 388–405 (2015).
Bechmann, I., Galea, I. & Perry, V. H. What is the blood-brain barrier (not)? Trends Immunol. 28, 5–11 (2007).
Perry, V. H., Anthony, D. C., Bolton, S. J. & Brown, H. C. The blood-brain barrier and the inflammatory response. Mol. Med. Today 3, 335–341 (1997).
Billingham, R. E. & Boswell, T. Studies on the problem of corneal homografts. Proc. R. Soc. B Biol. Sci. 141, 392–406 (1953).
Galea, I., Bechmann, I. & Perry, V. H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).
Rothhammer, V. & Quintana, F. J. Control of autoimmune CNS inflammation by astrocytes. Semin. Immunopathol. 37, 625–638 (2015).
Schreiner, B. et al. Astrocyte depletion impairs redox homeostasis and triggers neuronal loss in the adult CNS. Cell Rep. 12, 1377–1384 (2015).
Ransohoff, R. M. & El Khoury, J. Microglia in Health and Disease. Cold Spring Harb. Perspect. Biol. 8 (2015).
Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).
Kivisakk, P. et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann. Neurol. 65, 457–469 (2009).
Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334 (2005).
Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).
Dominguez, P. M. & Ardavin, C. Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation. Immunol. Rev. 234, 90–104 (2010).
Neal, J. W. & Gasque, P. How does the brain limit the severity of inflammation and tissue injury during bacterial meningitis? J. Neuropathol. Exp. Neurol. 72, 370–385 (2013).
Acknowledgements
This work was supported by grants from the Swiss national science foundation (310030_146130 and 316030_150768 to B.B.), the European Union, FP7 ITN_NeuroKine and the European Union FP7 project TargetBraIn (279017) (B.B.), the University Priority Project Translational Cancer Research (B.B.) and in part by a National Institute of Allergy and Infectious Diseases Grant R37 AI107494-01 (to J.G.).
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Becher, B., Spath, S. & Goverman, J. Cytokine networks in neuroinflammation. Nat Rev Immunol 17, 49–59 (2017). https://doi.org/10.1038/nri.2016.123
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DOI: https://doi.org/10.1038/nri.2016.123
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