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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2020

01-12-2020 | Glaucoma | Research

Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA/2J mice

Authors: Jeffrey M. Harder, Pete A. Williams, Catherine E. Braine, Hongtian S. Yang, Jocelyn M. Thomas, Nicole E. Foxworth, Simon W. M. John, Gareth R. Howell

Published in: Journal of Neuroinflammation | Issue 1/2020

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Abstract

Background

The risk of glaucoma increases significantly with age and exposure to elevated intraocular pressure, two factors linked with neuroinflammation. The complement cascade is a complex immune process with many bioactive end-products, including mediators of inflammation. Complement cascade activation has been shown in glaucoma patients and models of glaucoma. However, the function of complement-mediated inflammation in glaucoma is largely untested. Here, the complement peptide C3a receptor 1 was genetically disrupted in DBA/2J mice, an ocular hypertensive model of glaucoma, to test its contribution to neurodegeneration.

Methods

A null allele of C3ar1 was backcrossed into DBA/2J mice. Development of iris disease, ocular hypertension, optic nerve degeneration, retinal ganglion cell activity, loss of RGCs, and myeloid cell infiltration in C3ar1-deficient and sufficient DBA/2J mice were compared across multiple ages. RNA sequencing was performed on microglia from primary culture to determine global effects of C3ar1 on microglia gene expression.

Results

Deficiency in C3ar1 lowered the risk of degeneration in ocular hypertensive mice without affecting intraocular pressure elevation at 10.5 months of age. Differences were found in the percentage of mice affected, but not in individual characteristics of disease progression. The protective effect of C3ar1 deficiency was then overcome by additional aging and ocular hypertensive injury. Microglia and other myeloid-derived cells were the primary cells identified that express C3ar1. In the absence of C3ar1, microglial expression of genes associated with neuroinflammation and other immune functions were differentially expressed compared to WT. A network analysis of these data suggested that the IL10 signaling pathway is a major interaction partner of C3AR1 signaling in microglia.

Conclusions

C3AR1 was identified as a damaging neuroinflammatory factor. These data help suggest complement activation causes glaucomatous neurodegeneration through multiple mechanisms, including inflammation. Microglia and infiltrating myeloid cells expressed high levels of C3ar1 and are the primary candidates to mediate its effects. C3AR1 appeared to be a major regulator of microglia reactivity and neuroinflammatory function due to its interaction with IL10 signaling and other immune related pathways. Targeting myeloid-derived cells and C3AR1 signaling with therapies is expected to add to or improve neuroprotective therapeutic strategies.
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Literature
1.
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081–90.PubMedCrossRef
2.
3.
4.
Kuehn MH, Kim CY, Ostojic J, Bellin M, Alward WL, Stone EM, et al. Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res. 2006;83(3):620–8.PubMedCrossRef
5.
Stasi K, Nagel D, Yang X, Wang RF, Ren L, Podos SM, et al. Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci. 2006;47(3):1024–9.PubMedCrossRef
6.
Tezel G, Yang X, Luo C, Kain AD, Powell DW, Kuehn MH, et al. Oxidative stress and the regulation of complement activation in human glaucoma. Invest Ophthalmol Vis Sci. 2010;51(10):5071–82.PubMedPubMedCentralCrossRef
7.
Morgan BP. The membrane attack complex as an inflammatory trigger. Immunobiology. 2016;221(6):747–51.PubMedCrossRef
8.
Peng Q, Li K, Sacks SH, Zhou W. The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Inflamm Allergy Drug Targets. 2009;8(3):236–46.PubMedCrossRef
9.
Coulthard LG, Woodruff TM. Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J Immunol. 2015;194(8):3542–8.PubMedCrossRef
10.
Triantafilou K, Hughes TR, Triantafilou M, Morgan BP. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J Cell Sci. 2013;126(Pt 13):2903–13.PubMedCrossRef
11.
Laudisi F, Spreafico R, Evrard M, Hughes TR, Mandriani B, Kandasamy M, et al. Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1beta release. J Immunol. 2013;191(3):1006–10.PubMedPubMedCentralCrossRef
12.
Hawksworth OA, Li XX, Coulthard LG, Wolvetang EJ, Woodruff TM. New concepts on the therapeutic control of complement anaphylatoxin receptors. Mol Immunol. 2017;89:36–43.PubMedCrossRef
13.
Xie CB, Jane-Wit D, Pober JS. Complement membrane attack complex: new roles, mechanisms of action, and therapeutic targets. Am J Pathol. 2020;190(6):1138–50.PubMedCrossRefPubMedCentral
14.
Miyahara T, Kikuchi T, Akimoto M, Kurokawa T, Shibuki H, Yoshimura N. Gene microarray analysis of experimental glaucomatous retina from cynomologous monkey. Invest Ophthalmol Vis Sci. 2003;44(10):4347–56.PubMedCrossRef
15.
Bosco A, Anderson SR, Breen KT, Romero CO, Steele MR, Chiodo VA, et al. Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma. Mol Ther. 2018;26(10):2379–96.PubMedPubMedCentralCrossRef
16.
Jha P, Banda H, Tytarenko R, Bora PS, Bora NS. Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma. Mol Immunol. 2011;48(15-16):2151–8.PubMedPubMedCentralCrossRef
17.
Reinehr S, Reinhard J, Gandej M, Gottschalk I, Stute G, Faissner A, et al. S100B immunization triggers NFkappaB and complement activation in an autoimmune glaucoma model. Sci Rep. 2018;8(1):9821.PubMedPubMedCentralCrossRef
18.
Harder JM, Braine CE, Williams PA, Zhu X, MacNicoll KH, Sousa GL, et al. Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective. Proc Natl Acad Sci U S A. 2017;114(19):E3839–E48.PubMedPubMedCentralCrossRef
19.
Kuehn MH, Kim CY, Jiang B, Dumitrescu AV, Kwon YH. Disruption of the complement cascade delays retinal ganglion cell death following retinal ischemia-reperfusion. Exp Eye Res. 2008;87(2):89–95.PubMedCrossRef
20.
Silverman SM, Kim BJ, Howell GR, Miller J, John SW, Wordinger RJ, et al. C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury. Mol Neurodegener. 2016;11:24.PubMedPubMedCentralCrossRef
21.
Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest. 2011;121(4):1429–44.PubMedPubMedCentralCrossRef
22.
Howell GR, Soto I, Ryan M, Graham LC, Smith RS, John SW. Deficiency of complement component 5 ameliorates glaucoma in DBA/2J mice. J Neuroinflammation. 2013;10:76.PubMedPubMedCentralCrossRef
23.
Williams PA, Tribble JR, Pepper KW, Cross SD, Morgan BP, Morgan JE, et al. Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol Neurodegener. 2016;11:26.PubMedPubMedCentralCrossRef
24.
Howell GR, MacNicoll KH, Braine CE, Soto I, Macalinao DG, Sousa GL, et al. Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol Dis. 2014;71:44–52.PubMedPubMedCentralCrossRef
25.
26.
Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, et al. Complement C3aR inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer's disease. Neuron. 2018;100(6):1337–53 e5.PubMedPubMedCentralCrossRef
27.
Lian H, Litvinchuk A, Chiang AC, Aithmitti N, Jankowsky JL, Zheng H. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J Neurosci. 2016;36(2):577–89.PubMedPubMedCentralCrossRef
28.
Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, et al. NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron. 2015;85(1):101–15.PubMedCrossRef
29.
Jarlestedt K, Rousset CI, Stahlberg A, Sourkova H, Atkins AL, Thornton C, et al. Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxic-ischemic brain injury. FASEB J. 2013;27(9):3797–804.PubMedCrossRef
30.
Boos L, Campbell IL, Ames R, Wetsel RA, Barnum SR. Deletion of the complement anaphylatoxin C3a receptor attenuates, whereas ectopic expression of C3a in the brain exacerbates, experimental autoimmune encephalomyelitis. J Immunol. 2004;173(7):4708–14.PubMedCrossRef
31.
Humbles AA, Lu B, Nilsson CA, Lilly C, Israel E, Fujiwara Y, et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature. 2000;406(6799):998–1001.PubMedCrossRef
32.
Smith RS, Zabaleta A, Kume T, Savinova OV, Kidson SH, Martin JE, et al. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet. 2000;9(7):1021–32.PubMedCrossRef
33.
John SW, Smith RS, Savinova OV, Hawes NL, Chang B, Turnbull D, et al. Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci. 1998;39(6):951–62.PubMed
34.
John SW, Hagaman JR, MacTaggart TE, Peng L, Smithes O. Intraocular pressure in inbred mouse strains. Invest Ophthalmol Vis Sci. 1997;38(1):249–53.PubMed
35.
Savinova OV, Sugiyama F, Martin JE, Tomarev SI, Paigen BJ, Smith RS, et al. Intraocular pressure in genetically distinct mice: an update and strain survey. BMC Genet. 2001;2:12.PubMedPubMedCentralCrossRef
36.
Smith RSZA, Kume T, Savinova OV, Kidson SH, et al. General and specific histopathology. In: Smith RS, editor. Systemic evaluation of the mouse eye. New York: CRC Press; 2002. p. 265–97.
37.
Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, et al. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol. 2007;179(7):1523–37.PubMedPubMedCentralCrossRef
38.
Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, et al. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J Clin Invest. 2012;122(4):1246–61.PubMedPubMedCentralCrossRef
39.
Libby RT, Anderson MG, Pang IH, Robinson ZH, Savinova OV, Cosma IM, et al. Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Vis Neurosci. 2005;22(5):637–48.PubMedCrossRef
40.
Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nickells RW, et al. Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet. 2005;1(1):17–26.PubMedCrossRef
41.
Chou TH, Bohorquez J, Toft-Nielsen J, Ozdamar O, Porciatti V. Robust mouse pattern electroretinograms derived simultaneously from each eye using a common snout electrode. Invest Ophthalmol Vis Sci. 2014;55(4):2469–75.PubMedPubMedCentralCrossRef
42.
Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14(4):R36.PubMedPubMedCentralCrossRef
43.
Anders S, Pyl PT, Huber W. HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9.PubMedCrossRef
44.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.PubMedCrossRef
45.
Mo JS, Anderson MG, Gregory M, Smith RS, Savinova OV, Serreze DV, et al. By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma. J Exp Med. 2003;197(10):1335–44.PubMedPubMedCentralCrossRef
46.
Anderson MG, Nair KS, Amonoo LA, Mehalow A, Trantow CM, Masli S, et al. GpnmbR150X allele must be present in bone marrow derived cells to mediate DBA/2J glaucoma. BMC Genet. 2008;9:30.PubMedPubMedCentralCrossRef
47.
Porciatti V, Saleh M, Nagaraju M. The pattern electroretinogram as a tool to monitor progressive retinal ganglion cell dysfunction in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2007;48(2):745–51.PubMedCrossRef
48.
Nagaraju M, Saleh M, Porciatti V. IOP-dependent retinal ganglion cell dysfunction in glaucomatous DBA/2J mice. Invest Ophthalmol Vis Sci. 2007;48(10):4573–9.PubMedCrossRef
49.
Howell GR, Walton DO, King BL, Libby RT, John SW. Datgan, a reusable software system for facile interrogation and visualization of complex transcription profiling data. BMC Genomics. 2011;12:429.PubMedPubMedCentralCrossRef
50.
Vanlandewijck M, He L, Mae MA, Andrae J, Ando K, Del Gaudio F, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554(7693):475–80.PubMedCrossRef
51.
He L, Vanlandewijck M, Mae MA, Andrae J, Ando K, Del Gaudio F, et al. Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci Data. 2018;5:180160.PubMedPubMedCentralCrossRef
52.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929–47.PubMedPubMedCentralCrossRef
53.
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A Unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169(7):1276–90 e17.PubMedCrossRef
54.
Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, 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(1):253–71 e6.PubMedCrossRef
55.
Williams PA, Braine CE, Kizhatil K, Foxworth NE, Tolman NG, Harder JM, et al. Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma. Mol Neurodegener. 2019;14(1):6.PubMedPubMedCentralCrossRef
56.
Tribble JR, Harder JM, Williams PA, John SWM. Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2 J mice. Mol Brain. 2020;13(1):81.PubMedPubMedCentralCrossRef
57.
Williams PA, Braine CE, Foxworth NE, Cochran KE, John SWM. GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma. J Neuroinflammation. 2017;14(1):93.PubMedPubMedCentralCrossRef
58.
Carpanini SM, Torvell M, Morgan BP. Therapeutic inhibition of the complement system in diseases of the central nervous system. Front Immunol. 2019;10:362.PubMedPubMedCentralCrossRef
59.
Kim YU, Kinoshita T, Molina H, Hourcade D, Seya T, Wagner LM, et al. Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein. J Exp Med. 1995;181(1):151–9.PubMedCrossRef
60.
Fonseca MI, Chu SH, Hernandez MX, Fang MJ, Modarresi L, Selvan P, et al. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J Neuroinflammation. 2017;14(1):48.PubMedPubMedCentralCrossRef
61.
Fraser DA, Pisalyaput K, Tenner AJ. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem. 2010;112(3):733–43.PubMedCrossRef
62.
Colonna L, Parry GC, Panicker S, Elkon KB. Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity. Clin Immunol. 2016;163:84–90.PubMedPubMedCentralCrossRef
63.
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–78.PubMedCrossRef
64.
El Gaamouch F, Audrain M, Lin WJ, Beckmann N, Jiang C, Hariharan S, et al. VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice. Mol Neurodegener. 2020;15(1):4.PubMedPubMedCentralCrossRef
65.
Wang Y, Sun SN, Liu Q, Yu YY, Guo J, Wang K, et al. Autocrine complement inhibits IL10-dependent T-cell-mediated antitumor immunity to promote tumor progression. Cancer Discov. 2016;6(9):1022–35.PubMedPubMedCentralCrossRef
66.
Laffer B, Bauer D, Wasmuth S, Busch M, Jalilvand TV, Thanos S, et al. Loss of IL-10 promotes differentiation of microglia to a M1 phenotype. Front Cell Neurosci. 2019;13:430.PubMedPubMedCentralCrossRef
67.
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–7.PubMedPubMedCentralCrossRef
Metadata
Title
Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA/2J mice
Authors
Jeffrey M. Harder
Pete A. Williams
Catherine E. Braine
Hongtian S. Yang
Jocelyn M. Thomas
Nicole E. Foxworth
Simon W. M. John
Gareth R. Howell
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Glaucoma
Published in
Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-020-02011-z

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Retraction Note: Bone mesenchymal stem cell-derivedexosomal microRNA-29b-3p preventshypoxic-ischemic injury in rat brain byactivating the PTEN-mediated Aktsignaling pathway