Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut
Rachel Mak’Anyengo, … , Max Schnurr, Christian Bauer
Rachel Mak’Anyengo, … , Max Schnurr, Christian Bauer
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e96322. https://doi.org/10.1172/jci.insight.96322.
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Research Article Gastroenterology Immunology

Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut

Abstract

Inflammatory bowel disease (IBD) is associated with enhanced levels of the IL-1 family cytokines IL-1β and IL-18, which are activated by the Nlrp3 inflammasome. Here, we investigated the role of inflammasome-driven cytokine release on T cell polarization and DC differentiation in steady state and T cell transfer colitis. In vitro and in vivo data showed that IL-1β induces Th17 polarization and increases GM‑CSF production by T cells. Reduced IL-1β levels in Nlrp3–/– mice correlated with enhanced FLT3L levels and increased frequency of tolerogenic CD103+ DC. In the T cell transfer colitis model, Nlrp3 deficiency resulted in lower IL‑1β levels, reduced Th17 immunity, and less severe colitis. Unaltered IL-18 levels in both mouse strains pointed toward Nlrp3-independent processing. Importantly, cohousing revealed that the gut microbiome had no impact on the observed Nlrp3–/– phenotype. This study demonstrates that NLRP3 acts as a molecular switch of intestinal homeostasis by shifting local immune cells toward an inflammatory phenotype via IL-1β.

Authors

Rachel Mak’Anyengo, Peter Duewell, Cornelia Reichl, Christine Hörth, Hans‑Anton Lehr, Sandra Fischer, Thomas Clavel, Gerald Denk, Simon Hohenester, Sebastian Kobold, Stefan Endres, Max Schnurr, Christian Bauer

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Figure 1

NLRP3 deficiency favors development of tolerogenic CD103+ DC in a FLT3L-dependent manner.

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NLRP3 deficiency favors development of tolerogenic CD103+ DC in a FLT3L-...
(A) Frequency of total DC (CD11c+MHCII+) and percentage of CD103+ DC in lamina propria (LP), mesenteric lymph node (MLN), and spleen of WT and Nlrp3–/– mice under steady state conditions. (B) Development of CD103+ DC from BM precursors of WT and Nlrp3–/– mice using either the GM‑CSF + IL-4 or FLT3L protocol. (C) Cytokine secretion of BM‑derived DC from WT and Nlrp3–/– mice stimulated overnight with LPS. Levels of TNF-α, IL‑1β, and IL-12(p70) were measured in supernatants with ELISA. (D–F) WT and Nlrp3–/– mice were implanted with FLT3L-producing B16 tumor cells. (D and E) Expression profile of whole splenic subpopulations (D) and MACS-sorted CD11c+ DC populations (E) were analyzed by FACS. (F) CD11c-enriched DC were stimulated with LPS overnight. Secretion of TNF-α and IL-1β into supernatant was determined by ELISA. Data are shown as mean ± SEM; (A) WT n = 5, Nlrp3–/–, n = 5, 1 out of 3 experiments is shown; (B) WT, n = 4, Nlrp3–/–, n = 4, 1 out of 3 experiments shown; (C) WT (n = 4), Nlrp3–/– (n = 4), 1 out of 3 experiments shown; (D–F) WT (n = 2), Nlrp3–/– (n = 2), 1 out of 2 experiments is shown. *P < 0.05, **P < 0.01, ***P < 0.001, as assessed by unpaired 2-tailed Student’s t test.