Abstract
Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized
by demyelination and axonal loss. Demyelinating lesions are defined by cellular infiltrates composed
predominantly of T lymphocytes and two distinct types of myeloid cells, namely CNS infiltrating bone marrow-
derived macrophages (BMDM) and resident microglia. Understanding their interplay is essential to MS
pathogenesis, as T cell-produced cytokines and chemokines promote myeloid cell populations to produce toxic
factors and strip myelinated axons, culminating in tissue damage. However, how T cells instruct myeloid cells,
as well as the relative contributions of BMDM and microglia to tissue damage and disability, are unclear.
Specifically how Th1 and Th17 cells, both found in MS patients, affect BMDM and/or microglia to express toxic
functions, as well as strip and phagocyte myelin, are still poorly understood. The overall goal of this proposal is
to define in vivo mechanisms that regulate microglia and BMDM to actively participate in the demyelinating
process.
Using a unique murine virus encephalomyelitis model in which microglia mediate demyelination in the absence
of BMDM and Th17 response, this proposal will define how distinct T cell functions specifically promote
microglia-mediated demyelination. This model provides a unique tool to dissect how Th1 versus Th17 cells
regulate microglia effector functions during demyelination. Based on our preliminary data, we hypothesize that
strict Th1 conditions drive microglia to mediate demyelination, while Th17 response can modify this effect by
altering microglial pathogenic functions and promoting BMDM-mediated demyelination. Aim 1 will test how
microglial responsiveness to T cell-derived IFN-¿ regulates their demyelinating function independent of BMDM.
More specifically, this aim will define the contribution of microglia oxidative burst to myelin damage, as well as
determine whether TREM-2 modulation of microglial phagocytic functions can contribute to demyelination. Aim
2 will reveal how Th17 cells alters microglia effector functions and myelin damage, in the presence or absence
of BMDM, and whether this effect is directly dependent upon IL-17 and/or GM-CSF secretion. Gene array
analysis will also characterize phenotypic markers associated with the pathogenic versus protective functions
of microglia in a distinct inflammatory environment. By revealing how microglia respond to prominent T cell
cytokines, this proposal will provide new insights into the direct contribution of microglia to lesion formation in
MS patients, potentially leading to new therapeutic targets.