Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis

Abstract

Sex hormones promote immunoregulatory effects on multiple sclerosis. The current study evaluated estrogen effects on regulatory B cells and resident CNS microglia during experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate an estrogen-dependent induction of multiple regulatory B cell markers indicative of IL-10 dependent as well as IFN-γ dependent pathways. Moreover, although estrogen pretreatment of EAE mice inhibited the infiltration of pro-inflammatory cells into the CNS, it enhanced the frequency of regulatory B cells and M2 microglia. Our study suggests that estrogen has a broad effect on the development of regulatory B cells during EAE, which in turn could promote neuroprotection.

Mechanisms Involved in the Remyelinating Effect of Sildenafil

“…In agreement with previous results in EAE model (Pifarre et al 2014), recent studies have shown that the increased expression of IL-10 and promotion of M2 microglia phenopype after estrogen treatment promotes neuroprotection preventing EAE progression (Benedek et al 2016). Moreover, it has been shown that IL-10 increase expression resulted in attenuated inflammatory response, decreased microglia activation and less neurodegeneration in EAE model (Mayo et al 2016).…”

Estrogen protects both sexes against EAE by promoting common regulatory cell subtypes independent of endogenous estrogen

“…E2 pretreatment protected intact female C57B/6 mice, as previously reported (Benedek et al 2016). Male and OVX female C57B/6 mice were also significantly protected from EAE when E2 was administered 7 days prior to the induction of EAE compared to sham treated controls (Fig.…”

“…The frequency of CD4 + T cells was unchanged in male mice treated with E2 compared to sham treated mice (Fig 2b). Unlike B cells and T cells, the frequency of CD11b + (monocytes/macrophages) was significantly decreased in E2 treated OVX females and males (Fig 2a, p<0.05 and Fig 2b, p<0.0001), respectively, whereas intact female mice showed no significant difference in the frequency of CD11b + cells between E2 and sham treated mice (Benedek et al 2016). …”

“…The frequency of B cells (CD19 + ) was unchanged with E2 treatment during EAE in intact (Benedek et al 2016) and OVX females (Fig 2a) compared to E2 treated male mice that had a significance increase in the frequency of B cells (CD19 + ) compared to sham treated males (Fig 2b, p<0.05). Female mice, intact (Benedek et al 2016) or OVX (Fig 2a, p<0.05), treated with E2 had a significant decrease in the frequency of CD4 + T cells. The frequency of CD4 + T cells was unchanged in male mice treated with E2 compared to sham treated mice (Fig 2b).…”

“…E2 also regulates the immune system by increasing regulatory B and T cells (Benedek et al 2016; Polanczyk et al 2005). Treatment with E2 does not change the frequency of splenic B cells but it does shift the frequency of multiple regulatory B cell (Breg) subsets, including B10, Tim-1 + , and plasmablasts, (Benedek et al 2016) all of which produce IL-10 and can modulate T cell function (Ding et al 2011; Iwata et al 2011; Matsumoto et al 2014; Matsushita et al 2010). B10 cells also up regulate the expression of programmed death ligand 1 (PD-L1) which is critical for E2 dependent protection from EAE (Bodhankar et al 2013; Zhang et al 2015).…”