Journal
INTERNATIONAL IMMUNOLOGY
Volume 31, Issue 10, Pages 657-668Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxz004
Keywords
cholera toxin B; interleukin-1 beta; pyrin inflammasome
Categories
Funding
- Japan Society for the Promotion of Science [17H04088, 26293106, 15K08431, 18K07071, 17H05799, 17K19568, 15K19077, 25870401, 16K19585]
- Uehara Memorial Foundation
- Takeda Science Foundation
- AMED [JP19ek0109199]
- Ichiro Kanehara Foundation for the promotion of Medical Sciences and Medical care
- Inamori Foundation
- 2017 Wakayama Medical Award for Young Researchers
- Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University
- Institute for Enzyme Research, Joint Usage/Research Center, Tokushima University
- Grant for Joint Research Program of the Institute for Genetic Medicine Hokkaido University
- Grant for Joint Research Project of the Institute of Medical Science
- University of Tokyo
- Research Grant on Priority Areas from Wakayama Medical University
- Grants-in-Aid for Scientific Research [15K08431, 16K19585, 25870401, 18K07071, 17K19568, 17H04088, 17H05799, 26293106, 15K19077] Funding Source: KAKEN
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Cholera toxin B (CTB) is a subunit of cholera toxin, a bacterial enterotoxin secreted by Vibrio cholerae and also functions as an immune adjuvant. However, it remains unclear how CTB activates immune cells. We here evaluated whether or how CTB induces production of a pro-inflammatory cytokine, interleukin-1 beta (IL-1 beta). CTB induced IL-1 beta production not only from bone marrow-derived macrophages (BMMs) but also from resident peritoneal macrophages in synergy with O111:B4-derived lipopolysaccharide (LPS O111:B4) that can bind to CTB. Meanwhile, when prestimulated with O55:B5-derived LPS (LPS O55:B5) that fails to bind to CTB, resident peritoneal macrophages, @but not BMMs, produced IL-1 beta in response to CTB. The CTB-induced IL-1 beta production in synergy with LPS in both peritoneal macrophages and BMMs was dependent on ganglioside GM1, which is required for internalization of CTB. Notably, not only the NLRP3 inflammasome but also the pyrin inflammasome were involved in CTB-induced IL-1 beta production from resident peritoneal macrophages, while only the NLRP3 inflammasome was involved in that from BMMs. In response to CTB, a Rho family small GTPase, RhoA, which activates pyrin inflammasome upon various kinds of biochemical modification, increased its phosphorylation at serine-188 in a GM1-dependent manner. This phosphorylation as well as CTB-induced IL-1 beta productions were dependent on protein kinase A (PKA), indicating critical involvement of PKA-dependent RhoA phosphorylation in CTB-induced IL-1 beta production. Taken together, these results suggest that CTB, incorporated through GM1, can activate resident peritoneal macrophages to produce IL-1 beta in synergy with LPS through novel mechanisms in which pyrin as well as NLRP3 inflammasomes are involved.
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