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 3

NLRP3 deficiency promotes CD103+ DC differentiation in a T cell transfer colitis model and protects mice from Th17-associated tissue damage.

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NLRP3 deficiency promotes CD103+ DC differentiation in a T cell transfer...
Rag1–/– and Nlrp3–/– Rag1–/– mice were transferred with naive CD4+CD45Rbhi T cells from WT mice and sacrificed after 4 weeks. (A) Frequency of total CD11c+ DC and CD103+ DC in lamina propria, before and after T cell transfer, was analyzed by FACS. (B) Levels of FLT3L and GM-CSF in colon explants were analyzed by ELISA and qPCR. (C) Levels of proinflammatory cytokines IL-1β, IL-18, TNF-α, and IL-6 in colon explants were measured by ELISA. (D) Levels of IL-17 and IL‑22 in colon and frequency of lamina propria IL-17+CD4+ T cells were analyzed by ELISA and FACS, respectively. (E) Loss of body weight was monitored weekly and compared with appropriate healthy controls. (F) Clinical and histological scores at sacrifice. (G) H&E staining of representative colon sections. Scale bars: 100 μm. Three independent experiments were performed. (A and B) Rag1–/– (+ transfer), n = 11; Nlrp3–/– Rag1–/– (+ transfer), n = 9; Rag1–/–, n = 6; Nlrp3–/– Rag1–/–, n = 6. (C) Rag1–/– (+ transfer), n = 11; Nlrp3–/– Rag1–/– (+ transfer), n = 11; Rag1–/–, n = 6; Nlrp3–/– Rag1–/–, n = 6. (D) Rag1–/– (+ transfer), n = 6–11; Nlrp3–/– Rag1–/– (+ transfer), n = 5–11; Rag1–/–, n = 3–4; Nlrp3–/– Rag1–/–, n = 3–6. (E and F) Rag1–/– (+ transfer), n = 18; Nlrp3–/– Rag1–/– (+ transfer), n = 16; Rag1–/–, n = 6; Nlrp3–/– Rag1–/–, n = 6. Pooled data are presented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001, as assessed by unpaired 2-tailed Student’s t test. For the body weight analysis, *P < 0.05 according to 2-way ANOVA followed by Sidak’s multiple comparisons test.