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The contribution of the peripheral immune system to neurodegeneration

Nature Neuroscience volume 26, pages 942–954 (2023)Cite this article

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Abstract

Microglial cells are the major immune cells of the central nervous system (CNS), and directly react to neurodegeneration, but other immune cell types are also able to react to pathology and can modify the course of neurodegenerative processes. These mainly include monocytes/macrophages and lymphocytes. While these peripheral immune cells were initially considered to act only after infiltrating the CNS, recent evidence suggests that some of them can also act directly from the periphery. We will review the existing and emerging evidence for a role of peripheral immune cells in neurodegenerative diseases, both with and without CNS infiltration. Our focus will be on amyotrophic lateral sclerosis, but we will also compare to Alzheimer’s disease and Parkinson’s disease to highlight similarities or differences. Peripheral immune cells are easily accessible, and therefore may be an attractive therapeutic target for neurodegenerative diseases. Thus, understanding how these peripheral immune cells communicate with the CNS deserves deeper investigation.

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Fig. 1: Peripheral immune cells and their role in amyotrophic lateral sclerosis.
Fig. 2: Possible mechanisms by which peripheral immune cells could affect motor neurons and microglia, thus influencing ALS disease progression.

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References

  1. Michaud, J. P., Bellavance, M. A., Prefontaine, P. & Rivest, S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep. 5, 646–653 (2013). Seminal study using in vivo imaging to show the clearance of vascular amyloid beta by monocytes.

    Article  CAS  PubMed  Google Scholar 

  2. Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J. Neurosci. 31, 11159–11171 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Peter, I. et al. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 75, 939–946 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Villumsen, M., Aznar, S., Pakkenberg, B., Jess, T. & Brudek, T. Inflammatory bowel disease increases the risk of Parkinson’s disease: a Danish nationwide cohort study 1977–2014. Gut 68, 18–24 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Weimers, P. et al. Inflammatory bowel disease and Parkinson’s disease: a nationwide Swedish cohort study. Inflamm. Bowel Dis. 25, 111–123 (2019).

    Article  PubMed  Google Scholar 

  6. Beers, D. R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 103, 16021–16026 (2006). Seminal study in mice showing the contribution of microglial cells to ALS progression, but also that they do not initiate motor neuron degeneration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006). Study showing that motor neurons drive initiation of ALS and microglial cells/peripheral macrophages influence disease progression.

    Article  CAS  PubMed  Google Scholar 

  8. Wang, L., Sharma, K., Grisotti, G. & Roos, R. P. The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol. Dis. 35, 234–240 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251–253 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen, H. et al. Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann. Neurol. 58, 963–967 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Chen, H. et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch. Neurol. 60, 1059–1064 (2003).

    Article  PubMed  Google Scholar 

  12. Gao, X., Chen, H., Schwarzschild, M. A. & Ascherio, A. Use of ibuprofen and risk of Parkinson disease. Neurology 76, 863–869 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schrag, A., Horsfall, L., Walters, K., Noyce, A. & Petersen, I. Prediagnostic presentations of Parkinson’s disease in primary care: a case–control study. Lancet Neurol. 14, 57–64 (2015).

    Article  PubMed  Google Scholar 

  14. Devos, D. et al. Colonic inflammation in Parkinson’s disease. Neurobiol. Dis. 50, 42–48 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Pan, W. & Kastin, A. J. TNF transport across the blood–brain barrier is abolished in receptor knockout mice. Exp. Neurol. 174, 193–200 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Qin, L. et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55, 453–462 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Holmes, C. et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768–774 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dunn, N., Mullee, M., Perry, V. H. & Holmes, C. Association between dementia and infectious disease: evidence from a case–control study. Alzheimer Dis. Assoc. Disord. 19, 91–94 (2005).

    Article  PubMed  Google Scholar 

  19. Cui, C. et al. Associations between autoimmune diseases and amyotrophic lateral sclerosis: a register-based study. Amyotroph. Lateral Scler. Frontotemporal Degener. 22, 211–219 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Miller, Z. A. et al. Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: completing the picture. Neurol. Neuroimmunol. Neuroinflamm 3, e301 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  21. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Atanasio, A. et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production and glomerulonephropathy in mice. Sci. Rep. 6, 23204 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Burberry, A. et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl. Med. 8, 347ra393 (2016).

    Article  Google Scholar 

  24. O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sudria-Lopez, E. et al. Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects. Acta Neuropathol. 132, 145–147 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ahmad, L., Zhang, S. Y., Casanova, J. L. & Sancho-Shimizu, V. Human TBK1: a gatekeeper of neuroinflammation. Trends Mol. Med. 22, 511–527 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Griciuc, A. & Tanzi, R. E. The role of innate immune genes in Alzheimer’s disease. Curr. Opin. Neurol. 34, 228–236 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 43, 436–441 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Alam, M. M. et al. Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function. Cell Rep. 38, 110090 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Gardet, A. et al. LRRK2 is involved in the IFN-gamma response and host response to pathogens. J. Immunol. 185, 5577–5585 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Lee, H., James, W. S. & Cowley, S. A. LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson’s disease. Biochem. Soc. Trans. 45, 131–139 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gillardon, F., Schmid, R. & Draheim, H. Parkinson’s disease-linked leucine-rich repeat kinase 2R1441G mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience 208, 41–48 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Lall, D. et al. C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 109, 2275–2291 e2278 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McCauley, M. E. et al. C9orf72 in myeloid cells suppresses STING-induced inflammation. Nature 585, 96–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Taft, J. et al. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 184, 4447–4463 (2021). Study describing rare patients with systemic autoimmune disease linked to full deletion of TBK1, a gene for which haploinsufficiency is linked to ALS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marchlik, E. et al. Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality. J. Leukoc. Biol. 88, 1171–1180 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R. & Gitler, A. D. ALS genetics: gains, losses, and implications for future therapies. Neuron 108, 822–842 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007). Influential study showing self-renewal of microglia and that the CNS infiltration of myeloid cells from the periphery, measured in studies using irradiation, is an artifact of accidental BBB opening due to irradiation.

    Article  CAS  PubMed  Google Scholar 

  41. Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chiot, A. et al. Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival. Nat. Neurosci. 23, 1339–1351 (2020). Study showing that peripheral macrophages can influence disease progression, in ALS without infiltrating the CNS and that peripheral nerve macrophages and microglia react differently to the same motor neuron degenerating.

    Article  CAS  PubMed  Google Scholar 

  43. Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013). Study showing the microglial transcriptome modifications over the disease course in ALS mice, but also indicating that monocytes do not infiltrate the CNS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zondler, L. et al. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol. 132, 391–411 (2016). Study showing differences in ALS patient monocytes compared to controls, and that these modifications happen early on, even before disease onset in asymptomatic mutation carriers.

    Article  CAS  PubMed  Google Scholar 

  45. Parillaud, V. R. et al. Analysis of monocyte infiltration in MPTP mice reveals that microglial CX3CR1 protects against neurotoxic over-induction of monocyte-attracting CCL2 by astrocytes. J. Neuroinflammation 14, 60 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gao, L. et al. Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice. J. Exp. Med. 212, 469–480 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Martin, E., Boucher, C., Fontaine, B. & Delarasse, C. Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer’s disease models: effects of aging and amyloid pathology. Aging Cell 16, 27–38 (2017). Study showing that CNS infiltration of monocytes is weak and linked to aging in AD mice.

    Article  CAS  PubMed  Google Scholar 

  48. Reed-Geaghan, E. G., Croxford, A. L., Becher, B. & Landreth, G. E. Plaque-associated myeloid cells derive from resident microglia in an Alzheimer’s disease model. J. Exp. Med. 217, e20191374 (2020). Study showing in AD mice that infiltrating monocytes do not contribute to the parenchymal myeloid pool and microglial population.

  49. Yan, P. et al. Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease. J. Clin. Invest. 132, e152565 (2022). Study showing that only 6% of the parenchymal myeloid cells derive from infiltrating monocytes in AD mice.

  50. Chiu, I. M. et al. Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc. Natl Acad. Sci. USA 106, 20960–20965 (2009). Data showing progressive peripheral macrophage activation in peripheral nerves of ALS mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ben-Yaakov, K. et al. Axonal transcription factors signal retrogradely in lesioned peripheral nerve. EMBO J. 31, 1350–1363 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Baleriola, J. et al. Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell 158, 1159–1172 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007). Study showing the importance of peripheral myeloid cells to amyloid beta clearance.

    Article  CAS  PubMed  Google Scholar 

  54. Naert, G. & Rivest, S. CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer’s disease. J. Neurosci. 31, 6208–6220 (2011). Study showing the impact of peripheral myeloid cells in improving AD mouse cognitive decline.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489–502 (2006). Study showing the importance of peripheral myeloid cells to amyloid beta clearance.

    Article  CAS  PubMed  Google Scholar 

  56. Zhao, W. et al. Characterization of gene expression phenotype in amyotrophic lateral sclerosis monocytes. JAMA Neurol. 74, 677–685 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Du, Y. et al. Increased activation ability of monocytes from ALS patients. Exp. Neurol. 328, 113259 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Navarro, E. et al. Dysregulation of mitochondrial and proteolysosomal genes in Parkinson’s disease myeloid cells. Nat. Aging 1, 850–863 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Shigemizu, D. et al. Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through RNA sequencing analysis. Alzheimers Res Ther. 12, 87 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bradshaw, E. M. et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16, 848–850 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med. 6, 243ra286 (2014).

    Article  Google Scholar 

  62. Tian, L. et al. Decreased expression of cathepsin D in monocytes is related to the defective degradation of amyloid-beta in Alzheimer’s disease. J. Alzheimers Dis. 42, 511–520 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Zaghi, J. et al. Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy. Acta Neuropathol. 117, 111–124 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Beers, D. R., Henkel, J. S., Zhao, W., Wang, J. & Appel, S. H. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl Acad. Sci. USA 105, 15558–15563 (2008). Original study showing that CD4+ T cells are protective in ALS mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chiu, I. M. et al. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc. Natl Acad. Sci. USA 105, 17913–17918 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Engelhardt, J. I., Tajti, J. & Appel, S. H. Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch. Neurol. 50, 30–36 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Evans, F. L., Dittmer, M., de la Fuente, A. G. & Fitzgerald, D. C. Protective and regenerative roles of T cells in central nervous system disorders. Front. Immunol. 10, 2171 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kawamata, T., Akiyama, H., Yamada, T. & McGeer, P. L. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am. J. Pathol. 140, 691–707 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Lampson, L. A., Kushner, P. D. & Sobel, R. A. Major histocompatibility complex antigen expression in the affected tissues in amyotrophic lateral sclerosis. Ann. Neurol. 28, 365–372 (1990).

    Article  CAS  PubMed  Google Scholar 

  70. Troost, D., Van den Oord, J. J. & Vianney de Jong, J. M. Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis. Neuropathol. Appl. Neurobiol. 16, 401–410 (1990).

    Article  CAS  PubMed  Google Scholar 

  71. Weiss, F., Labrador-Garrido, A., Dzamko, N. & Halliday, G. Immune responses in the Parkinson’s disease brain. Neurobiol. Dis. 168, 105700 (2022).

    Article  CAS  PubMed  Google Scholar 

  72. Naor, S. et al. Development of ALS-like disease in SOD-1 mice deficient of B lymphocytes. J. Neurol. 256, 1228–1235 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Beers, D. R. et al. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134, 1293–1314 (2011). Original study showing hints that the Treg cell proportion correlates with disease progression in ALS patients.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Banerjee, R. et al. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS ONE 3, e2740 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sheean, R. K. et al. Association of regulatory T cell expansion with progression of amyotrophic lateral Sclerosis: a study of humans and a transgenic mouse model. JAMA Neurol. 75, 681–689 (2018). Extensive study in ALS mice and human patients showing the potential of Treg cells in improving disease progression.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Dansokho, C. et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139, 1237–1251 (2016).

    Article  PubMed  Google Scholar 

  77. Reynolds, A. D. et al. Regulatory T cells attenuate TH17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J. Immunol. 184, 2261–2271 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Brochard, V. et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009). Study showing evidence for T cell infiltration in postmortem brains of PD patients, and that such infiltration is neurotoxic in a PD mouse model.

    CAS  PubMed  Google Scholar 

  79. Williams, G. P. et al. CD4+T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson’s disease. Brain 144, 2047–2059 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Baruch, K. et al. Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology. Nat. Commun. 6, 7967 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Ito, M. et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565, 246–250 (2019).

    Article  CAS  PubMed  Google Scholar 

  82. Pasciuto, E. et al. Microglia Require CD4+ T cells to complete the fetal-to-adult transition. Cell 182, 625–640 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Coque, E. et al. Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons. Proc. Natl Acad. Sci. USA 116, 2312–2317 (2019). Study showing the negative impact of CD8+ T cells on motor neuron survival in ALS mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Komine, O. et al. Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes. Cell Death Differ. 25, 2130–2146 (2018). Study showing that blocking CD8+ T cells or NK cells does not influence disease progression in ALS mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cui, C. et al. Correlation between leukocyte phenotypes and prognosis of amyotrophic lateral sclerosis. Elife 11, e74065 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Nardo, G. et al. Counteracting roles of MHCI and CD8+ T cells in the peripheral and central nervous system of ALS SOD1G93A mice. Mol. Neurodegener. 13, 42 (2018). Study suggesting a possible role of CD8+ T cells, directly at the periphery, in peripheral nerves of ALS mice.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Beers, D. R. et al. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight 2, e89530 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Henkel, J. S. et al. Regulatory T lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol. Med. 5, 64–79 (2013). Study showing the potential of using Treg cell markers to identify patients with fast-progressing ALS.

    Article  CAS  PubMed  Google Scholar 

  89. Jin, M., Gunther, R., Akgun, K., Hermann, A. & Ziemssen, T. Peripheral proinflammatory TH1/TH17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis. Sci. Rep. 10, 5941 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Saresella, M. et al. T helper-17 activation dominates the immunologic milieu of both amyotrophic lateral sclerosis and progressive multiple sclerosis. Clin. Immunol. 148, 79–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Beers, D. R. et al. Tregs attenuate peripheral oxidative stress and acute phase proteins in ALS. Ann. Neurol. 92, 195–200 (2022).

  92. Camu, W. et al. Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): a phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine 59, 102844 (2020). Phase 2a trial showing safety of using IL-2 to increase Treg cells in ALS patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Garofalo, S. et al. Natural killer cells modulate motor neuron–immune cell crosstalk in models of amyotrophic lateral sclerosis. Nat. Commun. 11, 1773 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Murdock, B. J. et al. NK cells associate with ALS in a sex- and age-dependent manner. JCI Insight 6, e147129 (2021).

    PubMed  PubMed Central  Google Scholar 

  95. Zhang, Y. et al. Depletion of NK cells improves cognitive function in the Alzheimer disease mouse model. J. Immunol. 205, 502–510 (2020).

    Article  CAS  PubMed  Google Scholar 

  96. Earls, R. H. et al. NK cells clear alpha-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of alpha-synucleinopathy. Proc. Natl Acad. Sci. USA 117, 1762–1771 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Graves, M. C. et al. Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5, 213–219 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Trias, E. et al. Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS. JCI Insight 3, e123249 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Trias, E. et al. Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL-34, and SCF in amyotrophic lateral sclerosis. Glia 68, 1165–1181 (2020).

    Article  PubMed  Google Scholar 

  100. Trias, E. et al. Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis. J. Neuroinflammation 13, 177 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Trias, E. et al. Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS. JCI Insight 2, e95934 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Kovacs, M. et al. The pathogenic role of c-Kit+ mast cells in the spinal motor neuron-vascular niche in ALS. Acta Neuropathol. Commun. 9, 136 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, T. et al. Effects of chronic masitinib treatment in APPswe/PSEN1dE9 transgenic mice modeling Alzheimer’s disease. J. Alzheimers Dis. 76, 1339–1345 (2020).

    Article  CAS  PubMed  Google Scholar 

  104. Mora, J. S. et al. Long-term survival analysis of masitinib in amyotrophic lateral sclerosis. Ther. Adv. Neurol. Disord. 14, 17562864211030365 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Van Hove, H. et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22, 1021–1035 (2019).

    Article  PubMed  Google Scholar 

  108. Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bennett, M. L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl Acad. Sci. USA 113, E1738–E1746 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Lund, H. et al. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat. Commun. 9, 4845 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Staats, K. A., Borchelt, D. R., Tansey, M. G. & Wymer, J. Blood-based biomarkers of inflammation in amyotrophic lateral sclerosis. Mol. Neurodegener. 17, 11 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Moreno-Martinez, L., Calvo, A. C., Munoz, M. J. & Osta, R. Are circulating cytokines reliable biomarkers for amyotrophic lateral sclerosis? Int. J. Mol. Sci. 20, 2759 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hu, Y. et al. Increased peripheral blood inflammatory cytokine levels in amyotrophic lateral sclerosis: a meta-analysis study. Sci. Rep. 7, 9094 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Buttini, M., Limonta, S. & Boddeke, H. W. Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain. Neurochem. Int. 29, 25–35 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Quan, N. & Banks, W. A. Brain-immune communication pathways. Brain Behav. Immun. 21, 727–735 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Liu, X. et al. Cell-type-specific interleukin-1 receptor-1 signaling in the brain regulates distinct neuroimmune activities. Immunity 50, 317–333 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Moreno-Martinez, L. et al. Circulating cytokines could not be good prognostic biomarkers in a mouse model of amyotrophic lateral sclerosis. Front Immunol. 10, 801 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gowing, G., Dequen, F., Soucy, G. & Julien, J. P. Absence of tumor necrosis factor-alpha does not affect motor neuron disease caused by superoxide dismutase-1 mutations. J. Neurosci. 26, 11397–11402 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Han, Y., Ripley, B., Serada, S., Naka, T. & Fujimoto, M. Interleukin-6 deficiency does not affect motor neuron disease caused by superoxide dismutase-1 mutation. PLoS ONE 11, e0153399 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Nguyen, M. D., Julien, J. P. & Rivest, S. Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1β in neurodegeneration. Ann. Neurol. 50, 630–639 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Guttenplan, K. A. et al. Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model. Nat. Commun. 11, 3753 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Fulling, C., Dinan, T. G. & Cryan, J. F. Gut microbe to brain signaling: what happens in vagus. Neuron 101, 998–1002 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30, 492–506 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Wang, X. et al. Evidences for vagus nerve in maintenance of immune balance and transmission of immune information from gut to brain in STM-infected rats. World J. Gastroenterol. 8, 540–545 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Burberry, A. et al. C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature 582, 89–94 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The author’s research is supported by grants from the Fondation pour la Recherche Médicale (FRM, Equipe FRM EQU202103012581), the ALS association (ALSA, 20-IIA-530), NRJ-Institut de France, Fondation Thierry Latran, l’ARMC, S.L.A.F.R., ‘La longue route des malades de la SLA’, ‘Un pied devant l’autre’, Ferblanc and private donors to ALS at the ICM. F.B. was supported by a fellowship from the French ministry of research. We thank M. Mallat for helpful comments. Figures were partly drawn with free-to-use Servier Medical Art images available at https://smart.servier.com/.

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  1. These authors contributed equally: Félix Berriat, Christian S. Lobsiger.

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  1. Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière, Paris, France

    Félix Berriat, Christian S. Lobsiger & Séverine Boillée

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F.B., C.S.L. and S.B. wrote the manuscript.

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Berriat, F., Lobsiger, C.S. & Boillée, S. The contribution of the peripheral immune system to neurodegeneration. Nat Neurosci 26, 942–954 (2023). https://doi.org/10.1038/s41593-023-01323-6

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