Sepsis with its complications is a major challenge in contemporary medicine. Approximately 250,000 cases of sepsis lead to fatalities in the USA annually at huge costs for the healthcare system. Depending on the standards of medical care, the worldwide mortality rates in septic humans range from 30% to 70% with an aggregate mortality rate of ~50%. NLRP3 is a key component of the macromolecular signaling complex called the inflammasome that promotes caspase 1-dependent production of IL-1? pro-inflammatory cytokine involved in the development of sepsis. Although the factors leading to NLRP3 inflammasome activation have been extensively studied, the mechanisms for negatively regulating the activation of the NLRP3 inflammasome, and thus, controlling sepsis, are not known. We found that NLRP3 is inhibited by ubiquitination by Cbl-b, an E3 ubiquitin ligase. The significance of this finding is demonstrated by the observation that that lipopolysaccharide (LPS) injection or cecal ligation and puncture (CLP) induces a significant mortality in Cblb-/- mice compared to wild-type (WT) controls, and this increased mortality in Cblb-/- mice induced by LPS is blocked by an IL-1 receptor antagonist or by introducing NLRP3 deficiency. Therefore, our central hypothesis is that during sepsis, Cbl-b is autoubiquitinated/activated and ubiquitinates NLRP3, which in turn inhibits NLRP3 and attenuates NLRP3-mediated innate responses. We propose to determine 1) how Cbl-b regulates NLRP3 inflammasome activation; 2) whether and how Cbl-b controls non-canonical NLRP3 inflammasome in vivo using CLP-induced sepsis and LPS-induced septic shock as the study models. Understanding the role of Cbl-b in regulating the NLRP3 inflammasome-mediated signaling pathway will provide novel insights and therapeutic strategies to combat sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI121196-05
Application #
9717187
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Minnicozzi, Michael
Project Start
2017-11-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Tang, Juan; Lin, Guoxin; Langdon, Wallace Y et al. (2018) Regulation of C-Type Lectin Receptor-Mediated Antifungal Immunity. Front Immunol 9:123
Tang, Rong; Langdon, Wallace Y; Zhang, Jian (2018) Regulation of immune responses by E3 ubiquitin ligase Cbl-b. Cell Immunol :