Gender Differences, Hormones and Sex Chromosomes Oral Presentation

PS12.05 - p38 MAP kinase signaling in microglia plays a sex-specific protective role in CNS autoimmunity by regulating microglial transcriptional states

Speakers
  • D. Krementsov
Authors
  • M. McGill
  • A. Richman
  • J. Boyd
  • S. Frietze
  • D. Krementsov
Presentation Number
PS12.05
Presentation Topic
Gender Differences, Hormones and Sex Chromosomes
Lecture Time
10:12 - 10:24

Abstract

Background

Multiple sclerosis (MS) is three times more common in women, yet more severe in men, but the mechanisms underlying these sex differences remain mostly unknown. While MS is initiated by autoreactive T helper cells, CNS-infiltrating inflammatory myeloid cells are the proximal effector cells driving disease pathology. The role of CNS-resident myeloid cells, such as microglia, is less clear.

Objectives

We have previously shown that genetic ablation of p38α MAP kinase (p38) using LysM-Cre broadly in the myeloid lineage is protective in the autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE). Strikingly, this protection was seen in female mice and not males. Here, we sought to precisely define the mechanisms responsible.

Methods

We used multiple genetic approaches and bone marrow chimeras to ablate p38 in microglial cells, peripheral myeloid cells, or both, to study the effect on disease outcomes in EAE. Single cell and bulk transcriptional profiling, as well as flow cytometry, were used to identify molecular phenotypes of microglia.

Results

Deletion of p38 in both peripheral myeloid cells and microglia using Cx3cr1-Cre recapitulated the previous sex difference, with reduced EAE severity in females. Unexpectedly, Cx3cr1-Cre mediated deletion of p38 restricted to the bone marrow-derived peripheral compartment was protective in both sexes. However, deletion of p38 in microglia using inducible Cx3cr1-ER-Cre exacerbated EAE in males only, revealing opposing roles of p38 in microglia vs. peripheral myeloid cells. Single cell transcriptional profiling of microglia isolated from the inflamed CNS recapitulated recently described microglial diversity, identifying 8 distinct transcriptional states during acute EAE. Deletion of p38 resulted in enhanced transition from homeostatic to disease-associated microglial states, through the loss of expression of homeostatic genes such as Atf3, Rgs1, Btg2, and Neat1, with increased expression of disease-associated genes such as Cd74, Ccl5, and Spp1.

Conclusions

These results reveal the presence of a p38-dependent sex-specific molecular pathway in microglia that is protective in CNS autoimmunity through the regulation of microglial transcriptional states. Further, our findings suggest that autoimmunity in males and females may be driven by distinct cellular and molecular pathways, thus informing the design of novel future sex-specific therapeutic approaches.

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