NOD2 drives early IL-33–dependent expansion of group 2 innate lymphoid cells during Crohn’s disease–like ileitis
Carlo De Salvo, … , Séverine Vermeire, Theresa T. Pizarro
Carlo De Salvo, … , Séverine Vermeire, Theresa T. Pizarro
Published January 14, 2021
Citation Information: J Clin Invest. 2021;131(5):e140624. https://doi.org/10.1172/JCI140624.
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Concise Communication Gastroenterology Immunology

NOD2 drives early IL-33–dependent expansion of group 2 innate lymphoid cells during Crohn’s disease–like ileitis

Abstract

Innate lymphoid cells (ILCs) are enriched at barrier surfaces, including the gastrointestinal tract. While most studies have focused on the balance between pathogenic group 1 ILCs (ILC1s) and protective ILC3s in maintaining gut homeostasis and during chronic intestinal inflammation, such as Crohn’s disease (CD), less is known regarding ILC2s. Using an established murine model of CD-like ileitis, i.e., the SAMP1/YitFc (SAMP) mouse strain, we showed that ILC2s, compared with ILC1s and ILC3s, were increased within draining mesenteric lymph nodes and ilea of SAMP versus AKR (parental control) mice early, during the onset of disease. Gut-derived ILC2s from CD patients versus healthy controls were also increased and expanded, similarly to ILC1s, in greater proportion compared with ILC3s. Importantly, we report that the intracellular bacteria–sensing protein, nucleotide-binding oligomerization domaining–containing protein 2, encoded by Nod2, the first and strongest susceptibility gene identified for CD, promoted ILC2 expansion, which was dramatically reduced in SAMP mice lacking NOD2 and in SAMP mice raised under germ-free conditions. Furthermore, these effects occurred through a mechanism involving the IL-33/ST2 ligand-receptor pair. Collectively, our results indicate a functional link between NOD2 and ILC2s, regulated by the IL-33/ST2 axis, that mechanistically may contribute to early events leading to CD pathogenesis.

Authors

Carlo De Salvo, Kristine-Ann Buela, Brecht Creyns, Daniele Corridoni, Nitish Rana, Hannah L. Wargo, Chiara L. Cominelli, Peter G. Delaney, Alexander Rodriguez-Palacios, Fabio Cominelli, Séverine Vermeire, Theresa T. Pizarro

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Figure 1

Increased ILC2s during early disease in ileitis-prone SAMP mice that persists in the absence of adaptive immunity.

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Increased ILC2s during early disease in ileitis-prone SAMP mice that per...
(A) Gating strategy to detect total ILCs, identified as CD127+ and lineage– (Lin–) cells within the live CD45+ population (4-week-old mice, left) in draining MLNs of SAMP vs. AKR (control) mice, expressed as percentages (right) and (B) absolute numbers (n = 5–11). *P ≤ 0.05, ***P ≤ 0.001 by 2-tailed, unpaired Student’s t test. (C) Correlation by Pearson’s r between ILC frequency and disease severity ian SAMP and AKR mice (purple; n = 28). (D) ILC subsets, defined by GATA3+ (ILC2, orange), RORγt+ (ILC3, green), and GATA3–RORγt–T-bet+ (ILC1, purple) within the CD45+CD127+Lin– population (representative plots from 10-week-old mice, left), expressed as percentages (right) and (E) absolute numbers (n = 7–9). *P ≤ 0.05, ***P ≤ 0.001, ****P ≤ 0.0001 vs. 4-week-old mice or as indicated by the horizontal bars, by 2-way ANOVA with Tukey’s multiple-comparison post hoc test. (F) Ileitis severity in SAMP × Rag2–/– vs. WT (SAMP × Rag2+/+) mice (n = 7–10), with ILC (G) percentages (10-week-old mice shown) and (H) absolute numbers (n = 7). (I) Th2 cytokine expression, shown as fold-difference vs. AKR, which was set arbitrarily as 1 (n = 7–14). **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001 by 2-tailed, unpaired Student’s t test. Experiments were performed at least in duplicate.