Deletion of both the C3a and C5a receptors fails to protect against experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is an autoimmune disease in which inflammation, leukocyte infiltration, and ultimately, demyelination occur as a result of innate and adaptive immune-mediated mechanisms. The pathophysiological role of the complement system, a major component of innate immunity, in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for MS has been extensively examined. Previous studies from our lab have shown that the complement receptor for the anaphylatoxin C3a, but not for C5a plays an important role in EAE. Based on the important contributions of the complement anaphylatoxin receptors to other inflammatory conditions in the CNS, we reasoned that deletion of both receptors may reveal underlying interactions between them that are important to EAE pathology. We performed EAE in C3aR/C5aR double knockout mice (C3aR/C5aR −/− ) and observed delayed onset of disease but no attenuation of disease severity compared to wild type mice. Interestingly there was trend toward greater infiltration of CD4 + , but not CD8 + T cells, in C3aR/C5aR −/− mice with EAE, suggesting altered trafficking of these cells. Antigen-specific T cells isolated from C3aR/C5aR −/− mice during acute EAE produced elevated levels of TNF-α, but markedly reduced levels of IFN-γ and IL-12 compared to wild type mice. It remains unclear how the changes in these disease parameters contribute to the loss of the protective effect seen in C3aR −/− mice, however our data indicate a level of cross modulation between the C3aR and C5aR during EAE.

Role and mechanism of action of complement in regulating T cell immunity

“…Studies of a second DAF −/− mouse strain showed that EAE and enhanced T H 1 and T H 17 cell differentiation was rescued by either C3aR or C5aR deficiency (Liu et al , 2008). The latter result, as well as the finding by the same group that C3aR −/− C5aR −/− mice developed attenuated EAE compared with WT mice (Strainic et al , 2008), thus differed from the data cited above showing a lack of involvement of C5aR in EAE (Reiman et al , 2002, Morgan et al , 2004, Ramos, Wohler and Barnum, 2009)…”

“…Surprisingly, C5aR −/− mice were fully susceptible to EAE and treatment with a C5aR antagonist failed to protect from disease progression in rats (Reiman et al , 2002, Morgan et al , 2004) These latter results would suggest that C5aR does not play a role in EAE. The involvement of anaphylatoxin receptors in EAE was obscured somewhat by a recent report utilizing a C3aR −/− C5aR −/− double knockout mouse which suggested a certain degree of cross-modulation between the receptors in EAE as the double knockout seemed to lose at least a portion of the protective effect seen in the C3aR single knockout (Ramos, Wohler and Barnum, 2009)…”

Evidence for anti‐inflammatory effects of C5a on the innate IL‐17A/IL‐23 axis

“…On the other hand, there is abundant evidence demonstrating the detrimental role of IL‐17A in the pathogenesis of autoimmune diseases, implying that the release of IL‐17A must be tightly controlled in order to provide clearance of infectious pathogens without causing self‐inflicted persistent tissue inflammation. Conversely, the absence of the C5aR and C3aR has been associated with a trend toward greater disease activity in experimental autoimmune encephalomyelitis (41). However, other reports have favored either an enhancing or negligible influence of the complement system for the development of autoimmune disease (42–44).…”

The C5 Convertase Is Not Required for Activation of the Terminal Complement Pathway in Murine Experimental Cerebral Malaria

“…F, INF-␥, IL-6, and IL-1 levels were determined by ELISA (n ϭ 3-5 mice/group). G, brain tissue was isolated from PBS-perfused wild type and C3 Ϫ/Ϫ mice at day 6 (n ϭ 4/group) and subjected to flow cytometric analysis as described previously (43). The number of CD8 ϩ T cells in the brains of wild type and C3 Ϫ/Ϫ mice was not significantly different (p Ͼ 0.05, Student's t test).…”