TMEV-infection in susceptible strains of mice induces chronic demyelinating disease that is primarily mediated by CD4+ T cells [17, 30, 31]. However, epitope-specific CD4+ T cells can be protective or pathogenic depending on when activated T cells are available in conjunction with viral infection [23, 32, 33]. Interestingly, the level of IL-1β, induced following infection with TMEV, plays an important role in the pathogenesis of TMEV-induced demyelinating disease [18, 34]. Previously, it has been shown that administration of IL-1 to mice exacerbates the development of experimental autoimmune encephalomyelitis (EAE), the pathogenic immune mechanisms of which are similar to those of TMEV-induced demyelinating disease [35–37]. In addition, IL-1 appears to directly activate astrocytes and microglia to exacerbate neurodegeneration in non-immune-mediated diseases . Because IL-1β is induced via the innate immunity mediated by various TLRs and because the downstream IL-1 signals mediated via IL-1R also play an important role in the host defense [1, 4], we have investigated the role of IL-1β signals in the development of TMEV-induced demyelinating disease by assessing the effects of IL-1β administration and using IL-1R-deficient mice.
We have previously demonstrated that administration of IL-1β into resistant B6 mice renders the resistant mice susceptible to TMEV-induced demyelinating disease . The administration of IL-1β dramatically increased the level of IL-17 production in the CNS of the resistant mice, which do not produce a high level of Th17 cells following TMEV infection (Figure 1). This result is consistent with recent reports that IL-1β strongly promotes the development of IL-17-producing Th17 cells either directly or via the production of IL-6 [19, 39]. The presence of high levels of IL-17A in mice infected with TMEV exerts a strong pathogenic role by inhibiting the apoptosis of virus-infected cells, blocking cytolytic CD8+ T cell function, and elevating cellular infiltration to the CNS . Recently, it was also shown that the presence of FoxP3+ Treg cells that preferentially expand due to stimulation by IL-1β  is not beneficial for the development of TMEV-induced demyelinating disease; hence, these regulatory cells inhibit the protective anti-viral immune responses . Therefore, administration of IL-1β, resulting in a higher level of IL-1β, appears to promote the pathogenesis of TMEV-induced demyelinating disease in resistant B6 mice by elevating pathogenic Th17 and Treg responses to TMEV antigens. In addition, it is known that IL-1 directly activates astrocytes and microglia in the CNS , which are associated with the pathogenesis of TMEV-induced demyelinating disease [13, 43]. Furthermore, IL-1 mediates the loss of astroglial glutamate transport and drives motor neuron injury in the spinal cord during viral encephalomyelitis . The expression of IL-1R1 is upregulated in glial cells following TMEV infection , and thus the elevated receptor expression is likely to exert the detrimental effects seen as a result of IL-1 signaling on neurodegeneration and/or pathogenic immune responses.
In the absence of IL-1R1-mediated signals, resulting from engagements with the predominant cytokine IL-1β and weak cytokine IL-1α, strongly resistant B6 mice become susceptible to the development of TMEV-induced disease (Figure 2). Viral loads in the spinal cord are higher in the absence of IL-1R signals, suggesting that the presence of IL-1 signaling plays an important role in controlling viral persistence during the course of TMEV infection. The high viral loads also accompanied higher cellular infiltration into the CNS. Histopathological examinations of the virus-infected IL-1R-deficient B6 mice confirmed the elevated lymphocyte infiltration, demyelination and axonal losses in the CNS compared to control B6 mice (Figure 3). These results are consistent with previous reports indicating that either IL-1β- or IL-1RI-deficient mice are susceptible to various infections [1, 7, 8, 46]. These results collectively suggest that either an abnormally high level of IL-1β or the absence of IL-1-mediated signals lead to high viral loads and cellular infiltration to the CNS, resulting in the elevated development of TMEV-induced demyelinating disease. Therefore, a fine balance of IL-1β-mediated signaling appears to be important for protection from viral infections. It is also interesting to note that this viral model for MS is markedly different from the EAE model, which is not associated with microbial infections, in that a deficiency of IL-1R1 significantly reduces the development of demyelinating disease .
Despite many previous studies on the role of IL-1β signaling in viral infections, the underlying mechanisms of the signals involved in the protection from infection remain unclear. Previously, it has shown that IL-1-mediated signals augment T cell responses by increasing cellular infiltration, as well as upregulating cytokine production and co-stimulatory molecule expression in APCs [5, 47, 48]. However, our results showed that the cellular infiltration is elevated in IL-1R1 KO mice during the early stages of viral infection (Figure 2), although the anti-viral CD4+ T cell responses in the CNS of virus-infected IL-1R KO mice are lower without compromising either peripheral CD4+ T cell responses (Figure 5) or CNS CD8+ T cell responses (Figure 6). These results suggest that the APCs associated with CD4+ T cell responses in the CNS are primarily affected by the absence of IL-1-mediated signaling. Our previous studies strongly suggested that primarily the microglia and, to a certain extent, astrocytes, harbor viral loads and play important roles in the stimulation of the level and type of the CD4+ T cell response . In addition, it is known that IL-1 signaling affects the function of these cell types . Therefore, it is most likely that these cells play an important role in the development of anti-viral CD4+ T cell responses in the CNS during the early stage of viral infection. Because the cytokine production profile of APCs is altered in the absence of IL-1 signaling, perhaps due to the elevated expression of inhibitory molecules (Figure 7), similar mechanisms by CNS APCs may negatively affect the initial development and/or function of anti-viral T cells following viral infection. Regarding the underlying mechanisms, it is currently unclear how the deficiency in IL-1 signals enhances the expression of inhibitory molecules in APCs. However, we have observed that APCs from susceptible SJL mice expressed significantly higher levels of these molecules upon viral infection either in vitro or in vivo compared to cells from resistant B6 mice (data not shown), suggesting that the viral load may lead to the elevated expression. Therefore, it is most likely that the absence of IL-1 signals permits the initial elevation of viral load (Figure 4), and the higher viral load, in turn, leads to an eventual compromise in the efficiency of anti-viral T cell responses and functions. In contrast, the presence of excessive IL-1 signals preferentially triggers T cell responses that are unfavorable for the protection of the hosts from chronic viral persistence and the pathogenesis of demyelinating disease, as previously seen [17, 19].