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A myeloid–stromal niche and gp130 rescue in NOD2-driven Crohn’s disease

Author

Listed:
  • Shikha Nayar

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Joshua K. Morrison

    (Icahn School of Medicine at Mount Sinai)

  • Mamta Giri

    (Icahn School of Medicine at Mount Sinai)

  • Kyle Gettler

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Ling-shiang Chuang

    (Icahn School of Medicine at Mount Sinai)

  • Laura A. Walker

    (Icahn School of Medicine at Mount Sinai)

  • Huaibin M. Ko

    (The Mount Sinai Hospital
    The Mount Sinai Hospital
    Columbia University Medical Center)

  • Ephraim Kenigsberg

    (Icahn School of Medicine at Mount Sinai)

  • Subra Kugathasan

    (Emory University)

  • Miriam Merad

    (Icahn School of Medicine at Mount Sinai)

  • Jaime Chu

    (Icahn School of Medicine at Mount Sinai)

  • Judy H. Cho

    (Icahn School of Medicine at Mount Sinai)

Abstract

Crohn’s disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn’s disease1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment3. The risk alleles with the highest effect on Crohn’s disease are loss-of-function mutations in NOD24,5, which increase the risk of stricturing6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid–stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn’s disease, and suggest that gp130 blockade may benefit some patients with Crohn’s disease—potentially as a complement to anti-TNF therapy.

Suggested Citation

  • Shikha Nayar & Joshua K. Morrison & Mamta Giri & Kyle Gettler & Ling-shiang Chuang & Laura A. Walker & Huaibin M. Ko & Ephraim Kenigsberg & Subra Kugathasan & Miriam Merad & Jaime Chu & Judy H. Cho, 2021. "A myeloid–stromal niche and gp130 rescue in NOD2-driven Crohn’s disease," Nature, Nature, vol. 593(7858), pages 275-281, May.
  • Handle: RePEc:nat:nature:v:593:y:2021:i:7858:d:10.1038_s41586-021-03484-5
    DOI: 10.1038/s41586-021-03484-5
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    Cited by:

    1. Egle Kvedaraite & Magda Lourda & Natalia Mouratidou & Tim Düking & Avinash Padhi & Kirsten Moll & Paulo Czarnewski & Indranil Sinha & Ioanna Xagoraris & Efthymia Kokkinou & Anastasios Damdimopoulos & , 2024. "Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Fengfei Wu & Fangting Wu & Qian Zhou & Xi Liu & Jieying Fei & Da Zhang & Weidong Wang & Yi Tao & Yubing Lin & Qiaoqiao Lin & Xinghua Pan & Kai Sun & Fang Xie & Lan Bai, 2023. "A CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Jie Gao & Lei Wang & Jing Jiang & Qian Xu & Nianyi Zeng & Bingyun Lu & Peibo Yuan & Kai Sun & Hongwei Zhou & Xiaolong He, 2023. "A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Riley D. Metcalfe & Eric Hanssen & Ka Yee Fung & Kaheina Aizel & Clara C. Kosasih & Courtney O. Zlatic & Larissa Doughty & Craig J. Morton & Andrew P. Leis & Michael W. Parker & Paul R. Gooley & Tracy, 2023. "Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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