Citation

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-1b (IL-1b), 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 clarify the roles of inositol-requiring enzyme 1 alpha (IRE1a), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1b production in RPMs. In RPMs, CTB is incorporated into the
ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1a-deficient
RPMs show a significant impairment of CT- or CTB-induced IL-1b production, indicating that IRE1a is
required for CT- or CTB-induced IL-1b production in RPMs. This study demonstrates the critical roles of
IRE1a in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.