Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination

Abstract

SignificanceCXCL1 is a major neutrophil chemoattractant that binds to the chemokine receptor, CXCR2, on neutrophils and oligodendrocytes. Estrogen receptor β ligand treatment in a mouse model of multiple sclerosis induces an increase in peripheral and brain CXCL1 levels that correlate with an increase in axon remyelination. Oligodendrocyte progenitor recruitment and differentiation by CXCL1, in combination with attenuated IFN-γ production reducing apoptosis, may account for at least one avenue whereby estrogen receptor β ligands exert their clinical benefits.

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…These peripheral actions of estradiol, promoting general body health, may also contribute to neuroprotection. For instance, the estrogenic regulation of peripheral immune responses (Morales et al, 2006;Karim et al, 2018) may impact on the protective actions of the hormone on autoimmune demyelinating diseases; the estrogenic regulation of adiposity and peripheral body metabolism (Rettberg et al, 2014) may improve brain bioenergetics; and the estrogenic signaling on peripheral organs may induce the release of tissue-specific cytokines with neuroprotective actions. Estradiol also affects gut microbiome composition (Kaliannan et al, 2018), which in turn may change the microbiota-gut-brain axis communication under brain neurodegenerative conditions.…”

“…The ERβ selective agonist DPN is neuroprotective in the hippocampus of chronic hypertensive rats (Pietranera et al, 2016) and increases GFAP expression in astrocytes and decreases neuronal apoptosis in co-cultures of astrocytes and neurons exposed to oxygen glucose deprivation and reperfusion (Ma et al, 2016). Protective actions of DPN and other ERβ ligands, such has indazole-Cl and WAY-202041, have been also characterized in mouse models of multiple sclerosis, where they stimulate endogenous myelination and functional recovery (Atkinson et al, 2019;Khalaj et al, 2016;Karim et al, 2018Karim et al, , 2019) (see also Section 4.8). Furthermore, ERβ expressed in astrocytes mediates the protective effect of estradiol on neurons exposed to oxygen-glucose deprivation and reperfusion (Ma et al, 2016) and ERβ regulates inflammasome activation and protects from global cerebral ischemia in senescent female rats (de Rivero-Vaccari et al, 2016).…”

The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis

“…Interestingly, it has been shown that treatment of EAE-induced mice with ERβ ligands drastically reduced EAE severity. This correlated with increased astroglial production of CXCL1, leading to improved remyelination and neuroprotection [79].…”

Functional Effects of Cuprizone-Induced Demyelination in the Presence of the mTOR-Inhibitor Rapamycin

“…Coronal brain sections (bregma +0.85 to +0.95 mm, plates 23–24) with CC but no hippocampus (rostral slices) or sections (bregma −1.90 to −2.0 mm, plates 47–48) containing medial hippocampus (caudal slices) were used (Paxinos and Franklin, 2012; Karim et al, 2018). The brain slices were permeabilized, blocked in normal goat serum, and immunolabeled with primary antibodies shown in Table 1.…”

“…We address remyelination events using behavior, immunohistochemistry (IHC), electron microscopy and electrophysiology to further understand axon pathology and functional remyelination. Recognizing the potential for rapamycin to optimize the cuprizone model by producing more complete demyelination, we sought to characterize the effects of rapamycin treatment during cuprizone diet on axonal conduction and myelination in the largest white matter tract in the brain, the corpus callosum (CC), that is coherently affected by CPZ diet (Patel et al, 2013; Moore et al, 2014; Hasselmann et al, 2017; Lapato et al, 2017; Karim et al, 2018). In this study, mice were divided between three groups: normal diet (ND), demyelination (CPZ), and remyelination (CPZ + ND).…”