Vande Walle, L. | bioRxiv Science

bioRxiv2020

Inflammasome- and gasdermin D-independent IL-1β production mobilizes neutrophils to inhibit antitumor immunity

Interleukin-1{beta} (IL-1{beta}) is a central mediator of inflammation whose secretion typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL-1{beta} in promoting cancer progression in patients, but the underlying mechanisms are little understood. Here, we show a key role for IL-1{beta} in driving tumor progression in two distinct mouse tumor models. Notably, inflammasome activation and GSDMD were dispensable for the production of intratumoral bioactive IL-1{beta}, which promoted systemic mobilization and infiltration of neutrophils into tumors. Neutrophils recruited via IL-1{beta} suppressed the acquisition of an effector T-cell phenotype and subsequent antitumor immune response. Moreover, IL-1{beta} was essential for neutrophil accumulation upon antiangiogenic therapy, thereby contributing to therapy-induced immunosuppression. Antitumor immunity in the absence of IL-1{beta}-dependent neutrophil recruitment relied on immunostimulatory macrophages which promoted the infiltration and activation of cytotoxic T-cells. Overall, these results support a tumor-promoting role for IL-1{beta} through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for its release in tumors.

immunology↗

bioRxiv2019

MCC950/CRID3 potently targets the NACHT domain of wildtype NLRP3 but not disease-associated mutants for inflammasome inhibition

The NLRP3 inflammasome drives pathological inflammation in a suite of autoimmune, metabolic, malignant and neurodegenerative diseases. Additionally, NLRP3 gain-of-function point mutations cause systemic periodic fever syndromes that are collectively known as cryopyrin-associated periodic syndromes (CAPS). There is significant interest in the discovery and development of diarylsulfonylurea Cytokine Release Inhibitory Drugs (CRIDs) such as MCC950/CRID3, a potent and selective inhibitor of the NLRP3 inflammasome, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight in the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome. Here, we show that the NACHT domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labelling of the NACHT domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance, MCC950/CRID3 failed to inhibit NLRP3- driven inflammatory pathology in two mouse models of CAPS. Moreover, it abolished circulating levels of interleukin (IL)-1{beta} and IL-18 in LPS-challenged wildtype mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wildtype NLRP3 as the molecular target of MCC950/CRID3, and show that CAPS-related NLRP3 mutants escape efficient MCC950/CRID3 inhibition. Collectively, this work suggests that MCC950/CRID3-based therapies may effectively treat inflammation driven by wildtype NLRP3, but not CAPS-associated mutants.

immunology↗