Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis
Liming Mao, Atsushi Kitani, Eitaro Hiejima, Kim Montgomery-Recht, Wenchang Zhou, Ivan Fuss, Adrian Wiestner, Warren Strober
Liming Mao, Atsushi Kitani, Eitaro Hiejima, Kim Montgomery-Recht, Wenchang Zhou, Ivan Fuss, Adrian Wiestner, Warren Strober
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Research Article Gastroenterology

Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis

Abstract

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non–B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain–containing 3 (NLRP3) inflammasome. We found that bone marrow–derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A–mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti–IL-β or anakinra, an inhibitor of IL-1β signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn’s disease.

Authors

Liming Mao, Atsushi Kitani, Eitaro Hiejima, Kim Montgomery-Recht, Wenchang Zhou, Ivan Fuss, Adrian Wiestner, Warren Strober

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Figure 7

Inhibition of IL-1β signaling ameliorates TNBS colitis in BTK-KO mice.

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Inhibition of IL-1β signaling ameliorates TNBS colitis in BTK-KO mice. M...
Male BTK-KO mice (n = 5) were administered anakinra i.p. (0.5 mg/mouse/day) on day –1 and then 3 mg TNBS per rectum on days 0 and 2. Male BTK-KO mice (n = 5) and WT mice (n = 5) administered TNBS per rectum and not treated with anakinra served as controls. Mouse body weight loss (A), colon length (B), disease score (C), and histological damage (D) due to colitis were measured. Original magnification, ×100. (E) Mononuclear cells from MLNs were primed with LPS (1 μg/mL) for 12 hours and then stimulated with ATP (5 mM, 30 minutes) or nigericin (1 μM, 30 minutes). The culture supernatants were then subjected to ELISA for IL-1β and IL-6. (F) Colonic tissues were homogenized and the homogenates subjected to ELISAs for IL-1β and IL-6. *P < 0.05 and **P < 0.01, by 1-way ANOVA with multiple comparisons test. Data are presented as the mean ± SD and are representative of 3 independent experiments.