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

## TL;DR

The study explores how different types of macrophages, FoxP3, and IL-17A influence central nervous system (CNS) damage caused by herpes simplex virus type 1 (HSV-1) infection.

## Contribution

The study reveals distinct and non-redundant roles of macrophage subsets, FoxP3, and IL-17A in HSV-1-induced CNS demyelination.

## Key findings

- Combined depletion of macrophages and FoxP3 in HSV-IL-2-infected mice triggered CNS demyelination, while the same depletion in WT HSV-1 infection prevented demyelination.
- M1 macrophages are key drivers of plaque formation, as their absence prevented demyelination in both HSV-IL-2 and WT HSV-1 infections.
- M2 macrophages play a protective role, as their deficiency led to demyelination.

## Abstract

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.

Demyelinating diseases include a range of immunopathologic diseases in which myelin, the covering of nerve cell fibers in the central nervous system (CNS), is destroyed. While the roots of demyelination are not well understood, one hypothesis is that it may result from autoimmunity to CNS antigens triggered by environmental factors, with the activated immune response leading to myelin destruction. Multiple sclerosis (MS) is one of the major diseases associated with myelin sheath degradation. In the optic nerve, demyelination and inflammation cause visual and neurologic dysfunction associated with optic neuritis (ON), an initial manifestation and early prognostic indicator of MS in young adults. Macrophage plays a vital role in maintaining immune homeostasis in the CNS by preventing the development of autoaggressive T cells, which are responsible for both autoimmunity and tolerance. In our current study, we investigated the role(s) of TH17 and Treg in the presence and absence of macrophages on CNS demyelination. We demonstrated the essential role of M2 macrophages compared with M1 macrophages in maintaining immune homeostasis and effectively preventing CNS demyelination in ocularly infected mice.