The individual innate immune components, interleukin-6 and complement component C3, play a role in the development of acute seizures in the Theiler's murine encephalomyelitis virus-induced seizure model. We examined the mRNA expression of various other complement components, cytokines, chemokines, and major histocompatibility complex antigens both within brain and in isolated ramified microglial and infiltrating macrophage/activated microglial cell populations over a time course covering the first 3 days postinfection. We found that complement component C3 showed the greatest increase in expression in brain of all of the complement components assayed and its level of expression was higher in infiltrating macrophages/activated microglia than in ramified microglial cells.
Get full access to this article
View all access options for this article.
References
1.
AlexanderJJ, AndersonAJ, BarnumSR, et al.The complement cascade: Yin-Yang in neuroinflammation—neuro-protection and -degeneration. J Neurochem, 2008; 107:1169–1187.
2.
AlexopoulouL, HoltAC, MedzhitovR, et al.Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature, 2001; 413:732–738.
3.
AshhurstTM, van VredenC, NiewoldP, et al.The plasticity of inflammatory monocyte responses to the inflamed central nervous system. Cell Immunol, 2014; 291:49–57.
4.
BarnumSR. Complement biosynthesis in the central nervous system. Crit Rev Oral Biol Med, 1995; 6:132–146.
5.
BuenzEJ, SauerBM, Lafrance-CoreyRG, et al.Apoptosis of hippocampal pyramidal neurons is virus independent in a mouse model of acute neurovirulent picornavirus infection. Am J Pathol, 2009; 175:668–684.
6.
CarlsonNG, HillKE, TsunodaI, et al.The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: implications for multiple sclerosis. J Neuroimmunol, 2006; 174:21–31.
7.
ChuY, JinX, ParadaI, et al.Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci U S A, 2010; 107:7975–7980.
8.
CurranT, FranzaBRJr.Fos and Jun: the AP-1 connection. Cell, 1988; 55:395–397.
9.
CusickMF, LibbeyJE, PatelDC, et al.Infiltrating macrophages are key to the development of seizures following virus infection. J Virol, 2013; 87:1849–1860.
10.
DepboyluC, SchaferMK, SchwaebleWJ, et al.Increase of C1q biosynthesis in brain microglia and macrophages during lentivirus infection in the rhesus macaque is sensitive to antiretroviral treatment with 6-chloro-2',3'-dideoxyguanosine. Neurobiol Dis, 2005; 20:12–26.
11.
DietzscholdB, SchwaebleW, SchaferMK, et al.Expression of C1q, a subcomponent of the rat complement system, is dramatically enhanced in brains of rats with either Borna disease or experimental allergic encephalomyelitis. J Neurol Sci, 1995; 130:11–16.
12.
GabayC, LamacchiaC, and PalmerG. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol, 2010; 6:232–241.
13.
GasqueP, DeanYD, McGrealEP, et al.Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology, 2000; 49:171–186.
14.
GasqueP, FontaineM, and MorganBP. Complement expression in human brain. Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. J Immunol, 1995; 154:4726–4733.
15.
HarrisonJK, JiangY, ChenS, et al.Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A, 1998; 95:10896–10901.
16.
HosokawaM, KlegerisA, MaguireJ, et al.Expression of complement messenger RNAs and proteins by human oligodendroglial cells. Glia, 2003; 42:417–423.
17.
HoweCL, LaFrance-CoreyRG, MirchiaK, et al.Neuroprotection mediated by inhibition of calpain during acute viral encephalitis. Sci Rep, 2016; 6:28699.
18.
HoweCL, Lafrance-CoreyRG, SundsbakRS, et al.Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection. Sci Rep, 2012; 2:545.
19.
HoweCL, Lafrance-CoreyRG, SundsbakRS, et al.Inflammatory monocytes damage the hippocampus during acute picornavirus infection of the brain. J Neuroinflammation, 2012; 9:50.
20.
JungS, AlibertiJ, GraemmelP, et al.Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol, 2000; 20:4106–4114.
21.
KirkmanNJ, LibbeyJE, WilcoxKS, et al.Innate but not adaptive immune responses contribute to behavioral seizures following viral infection. Epilepsia, 2010; 51:454–464.
22.
KleinBD, FuYH, PtacekLJ, et al.c-Fos immunohistochemical mapping of the audiogenic seizure network and tonotopic neuronal hyperexcitability in the inferior colliculus of the Frings mouse. Epilepsy Res, 2004; 62:13–25.
23.
KonsmanJP, DrukarchB, and Van DamAM. (Peri)vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci (Lond), 2007; 112:1–25.
24.
LeeH, LeeS, ChoIH, et al.Toll-like receptors: sensor molecules for detecting damage to the nervous system. Curr Protein Pept Sci, 2013; 14:33–42.
25.
LibbeyJE, and FujinamiRS. Neurotropic viral infections leading to epilepsy: focus on Theiler's murine encephalomyelitis virus. Future Virol, 2011; 6:1339–1350.
26.
LibbeyJE, KennettNJ, WilcoxKS, et al.Interleukin-6, produced by resident cells of the central nervous system and infiltrating cells, contributes to the development of seizures following viral infection. J Virol, 2011; 85:6913–6922.
27.
LibbeyJE, KirkmanNJ, SmithMC, et al.Seizures following picornavirus infection. Epilepsia, 2008; 49:1066–1074.
28.
LibbeyJE, KirkmanNJ, WilcoxKS, et al.Role for complement in the development of seizures following acute viral infection. J Virol, 2010; 84:6452–6460.
29.
PaolicelliRC, BolascoG, PaganiF, et al.Synaptic pruning by microglia is necessary for normal brain development. Science, 2011; 333:1456–1458.
30.
Perales-LinaresR, and Navas-MartinS. Toll-like receptor 3 in viral pathogenesis: friend or foe?. Immunology, 2013; 140:153–167.
31.
RaivichG, JonesLL, KlossCU, et al.Immune surveillance in the injured nervous system: T-lymphocytes invade the axotomized mouse facial motor nucleus and aggregate around sites of neuronal degeneration. J Neurosci, 1998; 18:5804–5816.
32.
RansohoffRM, and CardonaAE. The myeloid cells of the central nervous system parenchyma. Nature, 2010; 468:253–262.
33.
Rezai-ZadehK, GateD, and TownT. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease?. J Neuroimmune Pharmacol, 2009; 4:462–475.
34.
RubioN, and Martin-ClementeB. Theiler's murine encephalomyelitis virus infection induces early expression of c-fos in astrocytes. Virology, 1999; 258:21–29.
35.
RubioN, and SierraA. Interleukin-6 production by brain tissue and cultured astrocytes infected with Theiler's murine encephalomyelitis virus. Glia, 1993; 9:41–47.
36.
ShastriA, BonifatiDM, and KishoreU. Innate immunity and neuroinflammation. Mediators Inflammation, 2013; 2013:342931.
37.
SinghiP. Infectious causes of seizures and epilepsy in the developing world. Dev Med Child Neurol, 2011; 53:600–609.
38.
SmithJA, DasA, RaySK, et al.Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull, 2012; 87:10–20.
TatematsuM, NishikawaF, SeyaT, et al.Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA. Nature Commun, 2013; 4:1833.
42.
TsunodaI, LaneTE, BlackettJ, et al.Distinct roles for IP-10/CXCL10 in three animal models, Theiler's virus infection, EAE, and MHV infection, for multiple sclerosis: implication of differing roles for IP-10. Mult Scler, 2004; 10:26–34.
43.
UedaT, RieuP, BrayerJ, et al.Identification of the complement iC3b binding site in the beta 2 integrin CR3 (CD11b/CD18). Proc Natl Acad Sci U S A, 1994; 91:10680–10684.
44.
VakevaA, MorganBP, TikkanenI, et al.Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium. Am J Pathol, 1994; 144:1357–1368.
45.
YenariMA, KauppinenTM, and SwansonRA. Microglial activation in stroke: therapeutic targets. Neurotherapeutics, 2010; 7:378–391.
46.
YuJX, BradtBM, and CooperNR. Constitutive expression of proinflammatory complement components by subsets of neurons in the central nervous system. J Neuroimmunol, 2002; 123:91–101.
47.
ZabelMK, and KirschWM. From development to dysfunction: microglia and the complement cascade in CNS homeostasis. Ageing Res Rev, 2013; 12:749–756.
48.
ZhangX, KimuraY, FangC, et al.Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood, 2007; 110:228–236.
49.
ZhangY, FengXH, and DerynckR. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature, 1998; 394:909–913.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
