A stress sensor IRE1a is required for bacterial exotoxin-induced interleukin-1ß production in tissue-resident macrophages

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1ß (IL-1ß), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarified the roles of IRE1a , an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1ß production from RPMs. In RPMs, CTB is incorporated into ER and induced ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1a -deficient RPMs showed a significant impairment of CT- or CTB-induced IL-1ß production, indicating that IRE1a was required for CT- or CTB-induced IL-1ß production from RPMs. This study demonstrates the critical roles of IRE1a in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages. Overall design: comprehensive analysis of CT or CTB-induced genes in LPS-primed RPMs, comprehensive analysis of CT or Tm-induced genes in resting RPMs