Estrogen Receptor α induces microRNA‐365 expression to attenuate classical macrophage activation

Abstract

The sex steroid hormone estrogen, besides its role in reproduction, has been reported as a potential regulator for immune responses. Albeit the increasing co‐morbidity associated with obesity, the pandemic threat marked with chronic inflammation and insulin resistance, only a handful of studies suggest estrogen may exert immune suppressive effect in this context. In this study, we report the first set of evidence to support that estrogen receptor alpha (ERα) signaling can selectively suppress classical activation of macrophages, which is the primary contributor to obesity‐induced chronic inflammation.First, our microRNA array analysis from macrophages subjected to polarized activation conditions revealed a set of microRNAs were actively regulated in macrophage classical activation. Bone marrow‐derived macrophages (BMDMs) stimulated with lipopolysaccharide/interferon gamma (LPS/INFγ) inflammatory responses (M1) and alternative activation (M2) by IL‐4/IL‐13 treatment. There were 33 miRNAs detected in naïve macrophage (M0), 156 miRNAs detected in M1, and 159 miRNAs detected in M2. Furthermore, there were 33 miRNAs displayed significant differential expression patterns in M1 or M2. Genomic analysis by surveying the promoters of these miRNAs identified a cluster of 10 miRNAs bearing ERα binding sites within 10 upstream kilobases. Interestingly, BMDMs subjected to 17β‐estradiol treatment exhibited suppressed M1 responses accompanied by significantly higher levels of ERa and miR‐365; whereas no detectable changes in ERa level in M2 activation. BMDMs treated with LPS/INFγ in the presence of 17β‐estradiol exhibited significantly lower levels of IL‐6, TNFα, and IL‐1β. Of note, miR‐365 level was significantly lower in M1 compared to M0, which was reversed by 17β‐estradiol treatment. Validation of the regulatory axis of ERa‐miR365 in macrophage classic activation will provide crucial evidence to support a novel paradigm shift in understanding the function of estrogen in obesity‐induced tissue inflammation and subsequent systemic disorders.Support or Funding InformationAmerican Diabetes Association (1‐13‐JF‐59 to B. Zhou) and National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK 1R01DK098662 to B. Zhou)