Sex-Specific Effects of Microglia-Like Cell Engraftment during Experimental Autoimmune Encephalomyelitis.

Jinming Han,Kai Zhou,Klas Blomgren,Harald Lund,Sreenivasa Raghavan Sankavaram,Robert A Harris,Xing-Mei Zhang,Ramil Hakim,Keying Zhu

doi:10.3390/ijms21186824

Abstract

Multiple sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that usually presents in young adults and predominantly in females. Microglia, a major resident immune cell in the CNS, are critical players in both CNS homeostasis and disease. We have previously demonstrated that microglia can be efficiently depleted by the administration of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice, with ensuing repopulation deriving from both the proliferation of residual CNS resident microglia and the engraftment of peripheral monocyte-derived microglia-like cells. In this study, tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ and Cx3cr1CreER/+ female and male mice. Experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, was induced by active immunization with myelin oligodendrocyte glycoprotein (MOG) one month after tamoxifen injections in Cx3cr1CreER/+Rosa26DTA/+ mice and Cx3cr1CreER/+ mice, a time point when the CNS niche was colonized by microglia derived from both CNS microglia and peripherally-derived macrophages. We demonstrate that engraftment of microglia-like cells following microglial depletion exacerbated EAE in Cx3cr1CreER/+Rosa26DTA/+ female mice as assessed by clinical symptoms and the expression of CNS inflammatory factors, but these findings were not evident in male mice. Higher major histocompatibility complex class II expression and cytokine production in the female CNS contributed to the sex-dependent EAE severity in mice following engraftment of microglia-like cells. An underestimated yet marked sex-dependent microglial activation pattern may exist in the injured CNS during EAE.

Highlights

Multiple sclerosis (MS) is a complex neuroinflammatory disorder of the central nervous system (CNS) associated with progressive and irreversible neurological dysfunctions [1]
We hypothesized that the engraftment of microglia-like cells following experimental microglia depletion could be beneficial for resolving ongoing neuroinflammation and promoting disease recovery in EAE. Immunizing both female and male Cx3cr1CreER/+Rosa26DTA/+ mice with myelin oligodendrocyte glycoprotein (MOG) to induce EAE, we report that exacerbated EAE in female mice results from the engraftment of microglia-like cells
In order to investigate the kinetic changes of microglial depletion and repopulation Cx3cr1CreER/+Rosa26DTA/+ and Cx3cr1CreER/+ mice were terminated at different time points after three consecutive subcutaneous tamoxifen injections, both male and female mice being used

Summary

Introduction

Multiple sclerosis (MS) is a complex neuroinflammatory disorder of the central nervous system (CNS) associated with progressive and irreversible neurological dysfunctions [1]. As specialized resident innate immune cells in the CNS, microglia provide neurotrophic support, contribute to normal myelinogenesis, synaptic pruning and refine neural circuits, thereby maintaining CNS homeostasis [2,3,4,5]. Microglial activation is widely noted in numerous neurological diseases such as MS [6,7], and comprehensive MS genomic mapping highlighted the inferred contribution of brain resident microglia [8]. The complexity of CNS innate cell populations may be amplified significantly in the context of neuroinflammation, reflecting heterogeneous responses by microglia and subsequent recruitment of diverse circulating immune cells into the injured CNS [11,12]. Considering the complex immunological features of MS, preclinical studies that recapitulate aspects of disease pathogenesis provide a valuable resource for understanding molecular mechanisms and exploring potential therapeutic interventions. Experimental autoimmune encephalomyelitis (EAE), despite several limitations, is the most widely used preclinical research model of MS [13]

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Conclusion