TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies
Matthew D. McGeough, … , Ariel E. Feldstein, Hal M. Hoffman
Matthew D. McGeough, … , Ariel E. Feldstein, Hal M. Hoffman
Published December 1, 2017; First published November 13, 2017
Citation Information: J Clin Invest. 2017;127(12):4488-4497. https://doi.org/10.1172/JCI90699.
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Categories: Research Article Immunology Inflammation

TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies

Abstract

The NLRP3 inflammasome is a protein complex responsible for caspase-1–dependent maturation of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function missense mutations in NLRP3 cause the disease spectrum known as the cryopyrin-associated periodic syndromes (CAPS). In this study, we generated Nlrp3-knockin mice on various KO backgrounds including Il1b/Il18-, caspase-1–, caspase-11– (Casp1/11-), and Tnf-deficient strains. The Nlrp3L351P Il1b–/– Il18–/– mutant mice survived and grew normally until adulthood and, at 6 months of age, exhibited marked splenomegaly and leukophilia. Injection of these mice with low-dose LPS resulted in elevated serum TNF levels compared with Nlrp3L351P Casp1/11–/– mice and Il1b–/– Il18–/– littermates. Treatment of Nlrp3A350V mice with the TNF inhibitor etanercept resulted in all pups surviving to adulthood, with normal body and spleen/body weight ratios. Nlrp3A350V Tnf–/– mice showed a similar phenotypic rescue, with marked reductions in serum IL-1β and IL-18, reduced myeloid inflammatory infiltrate in the skin and spleen, and substantial decreases in splenic mRNA expression of both inflammasome components (Nlrp3, Pycard, pro-Casp1) and pro-cytokines (Il1b, Il18). Likewise, we observed a reduction in the expression of both pro-Casp1 and pro-Il1b in cultured Nlrp3A350V Tnf–/– BM-derived DCs. Our data show that TNF is an important transcriptional regulator of NLRP3 inflammasome components in murine inflammasomopathies. Moreover, these results may have therapeutic implications for CAPS patients with partial responses to IL-1–targeted therapies.

Authors

Matthew D. McGeough, Alexander Wree, Maria E. Inzaugarat, Ariela Haimovich, Casey D. Johnson, Carla A. Peña, Raphaela Goldbach-Mansky, Lori Broderick, Ariel E. Feldstein, Hal M. Hoffman

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Figure 1

Role for caspase-1–dependent inflammatory mediators other than IL-1β and IL-18 in Nlrp3-mutant mice.

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Role for caspase-1–dependent inflammatory mediators other than IL-1β and...
Nlrp3L351P Il1b–/– Il18–/– mice had (A) elevated WBC numbers (each data point represents an individual mouse) and (B) splenomegaly, as evidenced by spleen weight/body weight ratios compared with Nlrp3L351P Casp1–/– mice (n = 5 mice/group). (C and D) IHC of splenic tissue showed increased MPO staining in Nlrp3L351P Il1b–/– Il18–/– mice and a similar degree of F4/80 staining in all groups. Images are representative of 6 mice per group (original magnification, ×20). Scale bar: 100 μm. *P < 0.05, by Kruskal-Wallis with Dunn’s multiple comparisons test, with the following comparisons: Casp1/11–/– versus Nlrp3A350V Il1b–/– Il18–/– mice; Nlrp3A350V Casp1/11–/– versus Nlrp3A350V Il1b–/– Il18–/– mice; and Il1b–/– Il18–/– versus Nlrp3A350V Il1b–/– Il18–/– mice. Data represent the mean ± SEM.