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