Bisphenol A (BPA) stimulates the interferon signaling and activates the inflammasome activity in myeloid cells

Abstract

Environmental factors contribute to the development of autoimmune diseases, including systemic lupus erythematosus (SLE), which exhibits a strong female bias (female-to-male ratio 9:1). However, the molecular mechanisms remain largely unknown. Because a feedforward loop between the female sex hormone estrogen (E2) and type I interferon (IFN-α/β)-signaling induces the expression of certain p200-family proteins (such as murine p202 and human IFI16) that regulate innate immune responses and modify lupus susceptibility, we investigated whether treatment of myeloid cells with bisphenol A (BPA), an environmental estrogen, could regulate the p200-family proteins and activate innate immune responses. We found that treatment of murine bone marrow-derived cells (BMCs) and human peripheral blood mononuclear cells with BPA induced the expression of ERα and IFN-β, activated the IFN-signaling, and stimulated the expression of the p202 and IFI16 proteins. Further, the treatment increased levels of the NLRP3 inflammasome and stimulated its activity. Accordingly, BPA-treatment of BMCs from non lupus-prone C57BL/6 and the lupus-prone (NZB × NZW)F1 mice activated the type I IFN-signaling, induced the expression of p202, and activated an inflammasome activity. Our study demonstrates that BPA-induced signaling in the murine and human myeloid cells stimulates the type I IFN-signaling that results in an induction of the p202 and IFI16 innate immune sensors for the cytosolic DNA and activates an inflammasome activity. These observations provide novel molecular insights into the role of environmental BPA exposures in potentiating the development of certain autoimmune diseases such as SLE.

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

“…Bisphenol A, a chemical which upregulates both type I IFN production and inflammasome activity in monocytes(21) may be linked with autoimmunity, but whether the two pathways intersected was not examined. One paper, which examined human PMBC populations, described decreased expression of NLRP3 in SLE vs. control samples(19).…”

“…Studies have identified type I IFN signaling as a negative regulator of inflammasome gene expression and activity in PBMCs and bone marrow-derived macrophages (BMDMs)(19, 20). However, other studies have identified correlations between elevations in IFN-induced gene expression and activation of the inflammasome in SLE(4, 21). Monocytes are sentinels of the IFN signature in autoimmune diseases(22) and are also an important source of inflammasome activation.…”

Tetrabromobisphenol A activates the hepatic interferon pathway in rats

“…MX1 and interferon regulatory factors) in model systems (Dabydeen et al, 2015; Fawzy et al, 2012; Schild-Hay et al, 2009). Exposure of myeloid cells to a related chemical, bisphenol A, also stimulated interferon signaling (Panchanathan et al, 2015). These TBBPA findings are supported by recent in vitro studies which showed TBBPA alterations in IFN production in human cells (Almughamsi and Whalen, 2016).…”

“…While TBBPA has little activity as an estrogen receptor agonist or antagonist (Hamers et al, 2006), a feedback loop between estrogen signaling and IFN signaling has been reported (Panchanathan et al, 2015, 2010). Upregulation of interferon pathways by TBBPA and tamoxifen could affect estrogen signaling and ultimately the development of uterine cancer.…”

Friend or Foe: Innate Sensing of HIV in the Female Reproductive Tract

“…Nevertheless, how hormonally induced changes in the endometrium influence sensing of HIV is an underexplored area of research. Interestingly, however, recent studies in mice have demonstrated that expression of IFI16 homologs increased upon activation of the estrogen receptor [140-142]. In addition, in pigs increased levels of estrogen in the endometrium associate with increased expression of ISGs, including Interferon Regulatory Factors (IRFs) and the IFN-inducible antiviral protein Mx1 [143].…”