Divergent roles of macrophage subsets, FoxP3, and IL-17A in HSV-1-induced CNS pathology

As a central player in neuroinflammation, macrophages play multifaceted roles such as antigen presentation, phagocytosis, production of cytokines/chemokines, and growth/neurotrophic factors. Our previous work demonstrated that ocular infection with a recombinant herpes simplex virus type 1 (HSV-1) expressing interleukin-2 (HSV-IL-2) causes CNS pathology, independently of macrophages in different mouse strains. In contrast, wild type (WT) HSV-1 infection induces CNS demyelination in a macrophage-dependent manner. Therefore, in this study, we have two mouse models infected with either HSV-IL-2 or WT HSV-1 to examine the outcome of the absence of IL-17A, FoxP3, macrophages, or combined macrophage and FoxP3 depletion on CNS demyelination. Our data reveals several notable findings: deletion of FoxP3 alone in mice infected with either HSV-IL-2 or WT HSV-1 did not induce CNS demyelination. However, combined depletion of macrophages and FoxP3 in HSV-IL-2-infected mice triggered CNS demyelination, whereas the same combined depletion in WT HSV-1 infection prevented demyelination. Additionally, macrophage depletion alone in WT HSV-1-infected mice induced CNS demyelination, highlighting the non-redundant protective role of macrophages in this model. To further elucidate the role of macrophages in CNS demyelination, we investigated which macrophage subtype is responsible for modulating demyelination using M1 and M2 knockout mice. Our results indicate that M1 macrophages are key drivers of plaque formation, as infection with either HSV-IL-2 or WT HSV-1 failed to cause CNS demyelination in the absence of M1 macrophages. Conversely, M2-deficient mice exhibited demyelination, suggesting a protective role for M2 macrophages. Finally, depletion of macrophages in IL-17A-deficient mice infected with HSV-IL-2 did not restore CNS demyelination, indicating that, unlike the macrophage-FoxP3 double depletion in the HSV-IL-2 model, the IL-17A-macrophage absence is beneficial. Taken together, these findings highlight the distinct and non-redundant roles of FoxP3, IL-17A, and macrophage subsets in modulating CNS pathology during HSV-1 infection and suggest that targeting M1 macrophage activation may be a promising strategy for limiting demyelination.