A stress sensor IRE1α is required for bacterial exotoxin-induced inflammasome activation in tissue-resident macrophages

Sasaki, I.; Fukuda-Ohta, Y.; Nakai, C.; Wakaki-Nishiyama, N.; Okamoto, C.; Orimo, T.; Okuzaki, D.; Morita, S.; Kaji, S.; Furuta, Y.; Hemmi, H.; Kato, T.; Yamamoto, A.; Tanaka, T.; Hoshino, K.; Fukuda, S.; Miyake, K.; Kuroda, E.; Ishii, K. J.; Iwawaki, T.; Furukawa, K.; Kaisho, T.

doi:10.1101/2023.07.06.547940

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bioRxiv · 10.1101/2023.07.06.547940

A stress sensor IRE1α is required for bacterial exotoxin-induced inflammasome activation in tissue-resident macrophages

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Abstract

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-1{beta} (IL-1{beta}), 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 IRE1, an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1{beta} production from RPMs. In RPMs, CTB is incorporated into ER and induced ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1-deficient RPMs showed a significant impairment of CT- or CTB-induced IL-1{beta} production, indicating that IRE1 was required for CT- or CTB-induced IL-1{beta} production from RPMs. This study first demonstrates the critical roles of IRE1 in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages. One sentence summaryIRE1 is required for NLRP3 and pyrin-mediated IL-1{beta} production

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Sasaki, I., Fukuda-Ohta, Y., Nakai, C., Wakaki-Nishiyama, N., Okamoto, C., Orimo, T., Okuzaki, D., Morita, S., Kaji, S., Furuta, Y., Hemmi, H., Kato, T., Yamamoto, A., Tanaka, T., Hoshino, K., Fukuda, S., Miyake, K., Kuroda, E., Ishii, K. J., Iwawaki, T., Furukawa, K., Kaisho, T.. 2023-07-07. A stress sensor IRE1α is required for bacterial exotoxin-induced inflammasome activation in tissue-resident macrophages. https://doi.org/10.1101/2023.07.06.547940

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