The Role of Interleukin-6 in the Expression of PD-1 and PDL-1 on Central Nervous System Cells following Infection with Theiler's Murine Encephalomyelitis Virus

Abstract

bInfection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) of susceptible mice results in an immune-mediated demyelinating disease which is considered a relevant viral model of human multiple sclerosis. We previously demonstrated that the expression of positive costimulatory molecules (CD40, CD80, and CD86) is higher on the microglia of TMEV-resistant C57BL/6 (B6) mice than the microglia of TMEV-susceptible SJL/J (SJL) mice. In this study, we analyzed the expression levels of the negative costimulatory molecules PD-1 and PDL-1 in the CNS of TMEV-infected SJL mice and B6 mice. Our results indicated that TMEV infection induces the expression of both PD-1 and PDL-1 on microglia and macrophages in the CNS but not in the periphery. The expression of PD-1 only on CNS-infiltrating macrophages and not on resident microglia was considerably higher (>4-fold) in TMEV-infected SJL mice than TMEV-infected B6 mice. We further demonstrated that interleukn-6 (IL-6) is necessary to induce the maximal expression of PDL-1 but not PD-1 after TMEV infection using IL-6-deficient mice and IL-6-transgenic mice in conjunction with recombinant IL-6. In addition, cells from type I interferon (IFN) receptor knockout mice failed to upregulate PD-1 and PDL-1 expression after TMEV infection in vitro, indicating that type I IFN signaling is associated with the upregulation. However, other IFN signaling may also participate in the upregulation. Taken together, these results strongly suggest that the expression of PD-1 and PDL-1 in the CNS is primarily upregulated following TMEV infection via type I IFN signaling and the maximal expression of PDL-1 additionally requires IL-6 signaling.

Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice

“…By contrast, studies using the BeAn-TMEV strain have shown that excessive IL-6 promotes pathogenic Th17 responses and viral persistence by preventing apoptosis of virus-infected cells [5,112]. IL-6, in interplay with other cytokines, also contributes to T cell exhaustion and inadequate viral elimination in TME [113,114]. However, sole IL-6 reduction following IL-10R neutralization is apparently insufficient to alter local CNS inflammatory responses in the present study.…”

Immunostimulatory effect of pepsin enzymatic extract from Porphyra yezoensis on murine splenocytes

“…A). Moreover, when we performed flow cytometric analysis of splenic cells with CD45 + CD11b + phenotype, common to macrophages and dendritic cells, we noticed a marked increase in the population of CD45 + CD11b + cells of PPEE‐treated splenocytes for both concentrations (7.0 ± 0.90% at 31.3 µg mL, −1 Fig. B, and 6.9 ± 0.30% at 62.5 µg mL, −1 Fig.…”

Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis

“…OASL1 causes T-cell suppression in persistent lymphocytic choriomeningitis virus infection of mice and is regarded as a new target for preventing chronic infectious diseases (43,44). In agreement with this idea, subpopulations of CNS-infiltrating macrophages have been demonstrated to reduce protective antiviral immunity by inducing T-cell exhaustion that leads to virus persistence in TMEV-infected mice (31). Besides this, M2-polarized cells have the ability to reduce antiviral immunity as described for human cytomegalovirus infection (1).…”