ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1β Activation During Streptococcus pneumoniae Infection

Abstract

Activating transcription factor-3 (ATF3) in the ER stress pathway induces cytokine production and promotes survival during gram-positive bacterial infection. IL-17A is a critical cytokine that is essential for clearance of Streptococcus pneumoniae. However, the mechanism by which ATF3 induces IL-17A production remains unknown. Here, we show that ATF3 induces IL-17A production via NLRP3 inflammasome-dependent IL-1β secretion. Survival rates were comparable in IL-17A-depleted and ATF3 KO mice but were lower than in WT mice treated with isotype control, indicating that ATF3 positively regulated IL-17A production. Indeed, ATF3 KO mice showed a marked reduction in IL-17A protein and mRNA expression compared to levels in WT mice. Moreover, mitochondrial IL-1β production by bone marrow-derived macrophages was significantly reduced in ATF3 KO mice as a result of the disruption of cellular ROS and Ca2+ homeostasis. Accordingly, ATF3 KO mice displayed diminished survival and bacterial clearance following S. pneumoniae infection. Taken together, these data suggest a mechanism in which macrophage ATF3 promotes IL-17A production in γδ T cells to rapidly induce host defenses during early S. pneumoniae infection.

Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer

“…Lee et al found that ATF3 −/− mice show decreased survival and bacterial clearance following S. pneumoniae infection. Macrophage ATF3 stimulates IL-17A production in lung γδ T cells to prompt host protection rapidly from early S. pneumoniae infection ( 54 ). Kim et al had found that oral treatment of metformin to either mouse with LPS-induced endotoxemia or ob/ob mice decreases the plasma and tissue levels of TNFα and IL-6 and upregulates ATF3 expression in spleen and lungs.…”

Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy

“…In addition to the point IL-17A activated ER stress under some pathological conditions, there were also reports indicated ER stress, as a critical proinflammation factor, promoted the secretion of IL-17A [ 11 , 30 , 37 ]. Therefore, we explored the effects of ER stress on IL-17A production in macrophage both in vivo and in vitro.…”

“…Previously, ATF3, as a key transcription factor in ER stress, positively regulated IL-17A production. After infected with S.pneumoniae, ATF3 KO mice showed a marked reduction of IL-17A expression in lung compared to that in WT mice [ 37 ]. Also, T lymphocytes and peripheral blood mononuclear cells responded to ERS by activating the IRE1/XBP1 signaling pathway, promoting secretions of IFN-γ, IL-17A, and IL-2 in a study about ulcerative colitis [ 30 ].…”

Taurine Attenuates Streptococcus uberis-Induced Bovine Mammary Epithelial Cells Inflammation via Phosphoinositides/Ca2+ Signaling

“…The data presented here are consistent with our previous study demonstrating significantly elevated cytoplasmic Ca 2+ by S. uberis infection (14). This is associated with the activation of PLC and hydrolyzation PIP2 to produce IP3 which bonds to Ca 2+ channels allowing Ca 2+ entry (41, 42). We found that the expression and activation of PLCγ1 the main isoform of PLC in epithelial cells (43) and cytoplasmic IP3 increases after S. uberis challenge.…”