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 2

Nlrp3-dependent IL-1β controls GM-CSF and FLT3L secretion by T cells and Th17 polarization.

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Nlrp3-dependent IL-1β controls GM-CSF and FLT3L secretion by T cells and...
(A) MACS-enriched splenic DC from Rag1–/– and Nlrp3–/– Rag1–/– mice were loaded with the MHC-II–restricted OVA323–339 peptide and cocultured with MACS-sorted naive CD4+ T cells from T cell receptor (TCR) transgenic OT‑II mice for 5 days. FLT3L, GM‑CSF, IFN-γ, and IL-17 levels in supernatants were measured by ELISA. (B) MACS-sorted splenic CD4+ T cells from WT mice were activated with anti-CD3 and anti-CD28 mAb in the absence or presence of IL-1β or IL-18 for 3 days. Secretion of FLT3L, GM-CSF, IL‑17, IFN-γ, and IL-22 was measured by ELISA. (C) Colon and mesenteric lymph nodes from WT and Nlrp3–/– mice at steady state were analyzed for FLT3L and GM-CSF production by ELISA. (D) CD4+ T cells from mesenteric lymph nodes and spleen were FACS-sorted, and mRNA expression levels of FLT3L and GM-CSF were analyzed by qPCR. Data are shown as mean ± SEM. (A) Pooled data from 3 independent experiments are shown; WT, n = 8; Nlrp3–/–, n = 8. (B) One out of 3 independent experiments is shown; WT, n = 4; Nlrp3–/–, n = 4. (C and D) Pooled data from 3 independent experiments are shown; WT, n = 6; Nlrp3–/–, n = 6. *P < 0.05, **P < 0.01, ***P < 0.001, as assessed by unpaired 2-tailed Student’s t test.