Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized
by focal T cell and myeloid cell infiltrates leading to demyelination and loss of neurologic function. Activated
microglia and macrophages are the predominant inflammatory cells in active or chronic MS plaques, and they
persist in secondary-progressive MS. Despite advances in our understanding of MS pathophysiology, there are
minimal disease-modifying treatments or preventions for innate-mediated, secondary-progressive forms of MS.
We recently found that mutually antagonistic pathways driven by TGFß and APOE signaling in microglia,
dictate a phenotypic switch between homeostatic (M0) and neurodegenerative (MGnD) phenotypes. Using a
systems biology approach, we identified major transcriptional and epigenetic regulators of M0- and MGnD-
microglia. Finally, we reveal a new role for TGFß-IFN¿ signaling in the reprogramming of peripheral monocytes
into microglia-like cells with the M0-molecular signature. Based on our published and preliminary data, we
hypothesize that modulating the APOE-TGFß/IFN¿ pathway will restore the homeostatic-tolerogenic microglia
and ameliorate EAE. We will address our hypothesis in the following aims:
Aim 1: Replenish M0-homeostatic microglia via APOE-TGFß/IFN¿ signaling in EAE
In this Aim, we will determine 1) the impact of TGFß/IFN¿ signaling on the replenishment of M0-microglia in
EAE; 2) the regulatory networks controlled by APOE-TGFß signaling underlying microglia phenotype regulation
in EAE; and 3) fate-map analysis of microglia phenotype switch during peak and recovery stage of EAE.
Aim 2: Reprogram monocytes into MG-like cells via APOE-TGFß/IFN¿ pathway in EAE and from MS
In this Aim, we will determine 1) whether targeting Apoe in Ly6CHi monocytes facilitates the acquisition of the
M0-microglial transcriptional program; 2) the molecular mechanisms underlying TGFß/IFN¿-mediated
reprogramming of Ly6CHi monocytes; and 3) whether modulation of the APOE-TGFß/IFN¿ pathway in
CD14+/CD16– monocytes isolated from MS subjects induces the M0-microglial transcriptional program to serve
as a novel therapeutic approach for progressive MS.
Successful completion will result in: 1) identification of molecular mechanisms mediated by APOE-TGFß/IFN¿
signaling in microglia and monocyte phenotype regulation that contribute to the development, progression and
resolution of EAE, and 2) understanding the role of APOE-TGFß/IFN¿ signaling in reprogramming of peripheral
monocytes into homeostatic microglia-like cells in EAE and from MS patients.