Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans
Tóm tắt
Major histocompatibility complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses, but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer’s disease (AD). Here, we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating ribosome affinity purification-qPCR analysis of 3–6- and 18–22-month-old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12–23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I-binding leukocyte immunoglobulin-like (Lilrs) and paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell -autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.
Tài liệu tham khảo
Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol. 1948;29:58–69.
Neuwelt EA, Clark WK. Unique aspects of central nervous system immunology. Neurosurgery. 1978;3:419–30.
Galea I, Bechmann I, Perry VH. What is immune privilege (not)? Trends Immunol. 2007;28:12–8.
Ransohoff RM, Cardona AE. The myeloid cells of the central nervous system parenchyma. Nature. 2010;468:253–62.
Vincenti I, Merkler D. New advances in immune components mediating viral control in the CNS. Curr Opin Virol. 2021;47:68–78.
Boulanger LM, Huh GS, Shatz CJ. Neuronal plasticity and cellular immunity: shared molecular mechanisms. Curr Opin Neurobiol. 2001;11:568–78.
Sheffield LG, Berman NEJ. Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging. 1998;19:47–55.
Hanke ML, Kielian T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci. 2011;121:367–87.
Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. Mol Immunol. 2011;48:1592–603.
Elward K, Gasque P. “Eat me” and “don’t eat me” signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system. Mol Immunol. 2003;40:85–94.
Radisky DC, Stallings-Mann M, Hirai Y, Bissell MJ. Single proteins might have dual but related functions in intracellular and extracellular microenvironments. Nat Rev Mol Cell Biol. 2009;10:228–34.
Stevens B, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.
Schafer DP, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.
Glynn MW, et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat Neurosci. 2011;14:442–51.
Yoshida TM, Wang A, Hafler DA. Basic principles of neuroimmunology. Semin Immunopathol. 2022;44(5):685–95.
Croese T, Castellani G, Schwartz M. Immune cell compartmentalization for brain surveillance and protection. Nat Immunol. 2021;22:1083–92.
Lampson LA. Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings. Microsc Res Tech. 1995;32:267–85.
Joly E, Mucke L, Oldstone MB. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science. 1991;253:1283–5.
Wong GH, Bartlett PF, Clark-Lewis I, Battye F, Schrader JW. Inducible expression of H-2 and Ia antigens on brain cells. Nature. 1984;310:688–91.
Shatz CJ. MHC class I: an unexpected role in neuronal plasticity. Neuron. 2009;64:40–5.
Rodgers JR, Cook RG. MHC class Ib molecules bridge innate and acquired immunity. Nat Rev Immunol. 2005;5:459–71.
Shiina T, Blancher A, Inoko H, Kulski JK. Comparative genomics of the human, macaque and mouse major histocompatibility complex. Immunology. 2017;150:127–38.
Ioannidu S, Walter L, Dressel R, Gunther E. Physical map and expression profile of genes of the telomeric class I gene region of the rat MHC. J Immunol. 2001;166:3957–65.
Shastri N, Schwab S, Serwold T. Producing nature’s gene-chips: the generation of peptides for display by MHC class I molecules. Annu Rev Immunol. 2002;20:463–93.
Cruz FM, Colbert JD, Merino E, Kriegsman BA, Rock KL. The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules. Annu Rev Immunol. 2017;35:149–76.
York IA, Rock KL. Antigen processing and presentation by the class I Major Histo COMPLEX. Annu Rev Immunol. 1996;14:369–96.
Rossjohn J, et al. T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2015;33:169–200.
Barrow AD, Trowsdale J. The extended human leukocyte receptor complex: diverse ways of modulating immune responses. Immunol Rev. 2008;224:98–123.
Burshtyn DN, Morcos C. The expanding spectrum of ligands for leukocyte Ig-like receptors. J Immunol. 2016;196:947–55.
Borges L, Hsu ML, Fanger N, Kubin M, Cosman D. A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol. 1997;159:5192–6.
Marffy AL, McCarthy AJ. Leukocyte immunoglobulin-like receptors (LILRs) on human neutrophils: modulators of infection and immunity. Front Immunol. 2020;11:857.
Hudson LE, Allen RL. Leukocyte Ig-like receptors - a model for MHC class I disease associations. Front Immunol. 2016;7:281.
Takai T. Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology. 2005;115:433–40.
Foster AJ, Bird JH, Timmer MSM, Stocker BL. The ligands of C-type lectins. In: Yamasaki S, editor. C-type lectin receptors in immunity. Tokyo: Springer Japan; 2016. p. 191–215.
Getahun A, Cambier JC. Of ITIMs, ITAMs, and ITAMis: revisiting immunoglobulin Fc receptor signaling. Immunol Rev. 2015;268:66–73.
Neumann H, Schmidt H, Cavalie A, Jenne D, Wekerle H. Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med. 1997;185:305–16.
Adelson JD, et al. Neuroprotection from stroke in the absence of MHCI or PirB. Neuron. 2012;73:1100–7.
Yong VW, Antel JP. Major histocompatibility complex molecules on glial cells. Semin Neurosci. 1992;4:231–40.
Needleman LA, Liu XB, El-Sabeawy F, Jones EG, McAllister AK. MHC class I molecules are present both pre- and postsynaptically in the visual cortex during postnatal development and in adulthood. Proc Natl Acad Sci U S A. 2010;107:16999–7004.
Huh GS, et al. Functional requirement for class I MHC in CNS development and plasticity. Science. 2000;290:2155–9.
Corriveau RA, Huh GS, Shatz CJ. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron. 1998;21:505–20.
Syken J, Grandpre T, Kanold PO, Shatz CJ. PirB restricts ocular-dominance plasticity in visual cortex. Science. 2006;313:1795–800.
Zalocusky KA, et al. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease. Nat Neurosci. 2021;24:786–98.
Rostami J, et al. Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain. J Neuroinflammation. 2020;17:119.
Goddery EN, et al. Microglia and perivascular macrophages act as antigen presenting cells to promote CD8 T cell infiltration of the brain. Front Immunol. 2021;12:726421.
Truong P, Heydari S, Garidou L, McGavern DB. Persistent viral infection elevates central nervous system MHC class I through chronic production of interferons. J Immunol. 2009;183:3895–905.
Holtman IR, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun. 2015;3:31.
Sobue A, et al. Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease. Acta Neuropathol Commun. 2021;9:1.
Krasemann S, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47:566-581.e569.
Paolicelli RC, et al. Microglia states and nomenclature: a field at its crossroads. Neuron. 2022;110:3458–83.
Hasel P, Rose IVL, Sadick JS, Kim RD, Liddelow SA. Neuroinflammatory astrocyte subtypes in the mouse brain. Nat Neurosci. 2021;24:1475–87.
Mangold CA, et al. CNS-wide sexually dimorphic induction of the major histocompatibility complex 1 Pathway with aging. J Gerontol A Biol Sci Med Sci. 2017;72:16–29.
VanGuilder Starkey HD, et al. Neuroglial expression of the MHCI pathway and PirB receptor is upregulated in the hippocampus with advanced aging. J Mol Neurosci. 2012;48:111–26.
Chucair-Elliott AJ, et al. Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia. Commun Biol. 2020;3:693.
Srinivasan R, et al. New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron. 2016;92:1181–95.
Yona S, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91.
Parkhurst CN, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155:1596–609.
Madisen L, et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2010;13:133–40.
Roh HC, et al. Simultaneous transcriptional and epigenomic profiling from specific cell types within heterogeneous tissues in vivo. Cell Rep. 2017;18:1048–61.
Jankowsky JL, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004;13:159–70.
Vartak RS, Rodin A, Oddo S. Differential activation of the mTOR/autophagy pathway predicts cognitive performance in APP/PS1 mice. Neurobiol Aging. 2019;83:105–13.
Chucair-Elliott AJ, et al. Tamoxifen induction of Cre recombinase does not cause long-lasting or sexually divergent responses in the CNS epigenome or transcriptome: implications for the design of aging studies. Geroscience. 2019;41:691–708.
Sahasrabuddhe V, Ghosh HS. Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain. Cell Rep. 2022;38:110252.
Ocañas SR, et al. Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex. Mol Neurobiol. 2022;59:4669–702.
Masser DR, et al. Hippocampal subregions exhibit both distinct and shared transcriptomic responses to aging and nonneurodegenerative cognitive decline. J Gerontol A Biol Sci Med Sci. 2014;69:1311–24.
Ocanas SR, et al. Minimizing the ex vivo confounds of cell-isolation techniques on transcriptomic and translatomic profiles of purified microglia. eNeuro. 2022. https://doi.org/10.1523/ENEURO.0348-21.2022.
Almanzar N, et al. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature. 2020;583:590–5.
Ximerakis M, et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat Neurosci. 2019;22:1696–708.
Virtanen P, et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat Methods. 2020;17:261–72.
Zhang Y, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–47.
Heiman M, Kulicke R, Fenster RJ, Greengard P, Heintz N. Cell type–specific mRNA purification by translating ribosome affinity purification (TRAP). Nat Protoc. 2014;9:1282–91.
Vasek MJ, et al. Microglia perform local protein synthesis at perisynaptic and phagocytic structures. bioRxiv. 2021;2001.2013.426577.
Stallcup KC, Springer TA, Mescher MF. Characterization of an anti-H-2 monoclonal antibody and its use in large-scale antigen purification. J Immunol. 1981;127:923–30.
GTEx-Consortium. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5.
Zhang Y, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 2016;89:37–53.
Olah M, et al. A transcriptomic atlas of aged human microglia. Nat Commun. 2018;9:539.
Sala Frigerio C, et al. The major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to abeta plaques. Cell Rep. 2019;27:1293-1306.e1296.
Baik SH, et al. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 2019;30:493-507.e496.
Zhou Y, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med. 2020;26:131–42.
Hammond TR, et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity. 2019;50:253-271.e256.
Keren-Shaul H, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017;169:1276-1290.e1217.
Marschallinger J, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020;23:194–208.
Li Q, et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron. 2019;101:207-223.e210.
Safaiyan S, et al. White matter aging drives microglial diversity. Neuron. 2021;109:1100-1117.e1110.
DePaula-Silva AB, et al. Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation. J Neuroinflammation. 2019;16:152.
Haage V, et al. Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma. Acta Neuropathol Commun. 2019;7:20.
Faraco G, Park L, Anrather J, Iadecola C. Brain perivascular macrophages: characterization and functional roles in health and disease. J Mol Med (Berl). 2017;95:1143–52.
Wang M, et al. The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci Data. 2018;5:180185.
Cribbs DH, et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation. 2012;9:179.
Pereira BI, et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun. 2019;10:2387.
Cary G, et al. Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains. medRxiv. 2022;2022.2012.2015.22283478.
Cebrian C, Loike JD, Sulzer D. Neuronal MHC-I expression and its implications in synaptic function, axonal regeneration and Parkinson’s and other brain diseases. Front Neuroanat. 2014;8:114.
Murakami G, et al. MHC class I in dopaminergic neurons suppresses relapse to reward seeking. Sci Adv. 2018;4:eaap7388.
Town T, Tan J, Flavell RA, Mullan M. T-cells in Alzheimer’s disease. Neuromolecular Med. 2005;7:255–64.
Gemechu JM, Bentivoglio M. T Cell recruitment in the brain during normal aging. Front Cell Neurosci. 2012;6:38.
Unger MS, et al. CD8(+) T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav Immun. 2020;89:67–86.
Jorfi M, Maaser-Hecker A, Tanzi RE. The neuroimmune axis of Alzheimer’s disease. Genome Med. 2023;15:6.
Navarro Negredo P, Brunet A. Unwanted help from T cells in the aging central nervous system. Nat Aging. 2021;1:330–1.
Proescholdt MG, et al. Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience. 2002;112:731–49.
Batterman KV, Cabrera PE, Moore TL, Rosene DL. T Cells Actively infiltrate the white matter of the aging monkey brain in relation to increased microglial reactivity and cognitive decline. Front Immunol. 2021;12:607691.
Groh J, et al. Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nature Aging. 2021;1:357–67.
Berry K, et al. B and T Lymphocyte Densities Remain Stable With Age in Human Cortex. ASN Neuro. 2021;13:17590914211018116.
Zhang X, et al. Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches. Immunity & Ageing. 2022;19:34.
Allen WE, Blosser TR, Sullivan ZA, Dulac C, Zhuang X. Molecular and spatial signatures of mouse brain aging at single-cell resolution. Cell. 2023;186:194-208.e118.
Benakis C, et al. T cells modulate the microglial response to brain ischemia. Elife. 2022;11:e82031.
Altendorfer B, et al. Transcriptomic profiling identifies CD8(+) T Cells in the brain of aged and Alzheimer’s disease transgenic mice as tissue-resident memory T cells. J Immunol. 2022;209:1272–85.
Rustenhoven J, et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell. 2021;184:1000-1016.e1027.
Dulken BW, et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature. 2019;571:205–10.
Haure-Mirande J-V, Audrain M, Ehrlich ME, Gandy S. Microglial TYROBP/DAP12 in Alzheimer’s disease: Transduction of physiological and pathological signals across TREM2. Mol Neurodegener. 2022;17:55.
Ennerfelt H, et al. SYK coordinates neuroprotective microglial responses in neurodegenerative disease. Cell. 2022;185:4135-4152.e4122.
Schafer DP, Stillman JM. Microglia are SYK of Abeta and cell debris. Cell. 2022;185:4043–5.
Wang S, et al. TREM2 drives microglia response to amyloid-beta via SYK-dependent and -independent pathways. Cell. 2022;185:4153-4169.e4119.
Shiroishi M, et al. Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Proc Natl Acad Sci U S A. 2006;103:16412–7.
Pluvinage JV, et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019;568:187–92.
Stojiljkovic MR, et al. Phenotypic and functional differences between senescent and aged murine microglia. Neurobiol Aging. 2019;74:56–69.
Streit WJ. Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci. 2006;29:506–10.
Talma N, Gerrits E, Wang B, Eggen BJL, Demaria M. Identification of distinct and age-dependent p16(High) microglia subtypes. Aging Cell. 2021;20:e13450.
Gems D, Kern CC. Is “cellular senescence” a misnomer? Geroscience. 2022;44:2461–9.