PUBLICATION

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

Authors
Nayar, S., Morrison, J.K., Giri, M., Gettler, K., Chuang, L.S., Walker, L.A., Ko, H.M., Kenigsberg, E., Kugathasan, S., Merad, M., Chu, J., Cho, J.H.
ID
ZDB-PUB-210401-13
Date
2021
Source
Nature   593(7858): 275-281 (Journal)
Registered Authors
Chuang, Ling-shiang (Felix), Chu, Jaime, Nayar, Shikha
Keywords
none
Datasets
GEO:GSE150498
MeSH Terms
  • Alleles
  • Animals
  • Collagen/metabolism
  • Crohn Disease/metabolism*
  • Cytokine Receptor gp130/antagonists & inhibitors
  • Cytokine Receptor gp130/metabolism*
  • Disease Models, Animal
  • Female
  • Fibroblasts/cytology
  • Fibroblasts/metabolism
  • Humans
  • Ileitis/metabolism
  • Indoles/pharmacology
  • Interleukin-11/metabolism
  • Lipopolysaccharide Receptors/metabolism
  • Macrophages/cytology
  • Macrophages/metabolism
  • Male
  • Myeloid Cells/cytology*
  • Myeloid Cells/metabolism
  • Nod2 Signaling Adaptor Protein/metabolism*
  • Receptor, Platelet-Derived Growth Factor alpha/metabolism
  • STAT3 Transcription Factor/metabolism
  • Stromal Cells/cytology*
  • Stromal Cells/metabolism
  • WT1 Proteins/metabolism
  • Zebrafish
  • Zebrafish Proteins/metabolism
PubMed
33789339 Full text @ Nature
Abstract
Crohn's disease (CD) is a chronic inflammatory intestinal disease, with frequent aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in pathogenicity1,2 with increases in intravasating monocytes correlated to anti-TNF treatment non-response3. The highest effect risk alleles are loss-of-function NOD24,5 mutations, which increase risk for stricturing6. However, mechanisms underlying NOD2-pathogenicity and salvage pathways in anti-TNF refractory patients remain largely uncharacterized. Here we show that NOD2 loss leads to dysregulated activated fibroblast and macrophage homeostasis by direct ex vivo analyses of patients carrying NOD2 risk alleles. CD14+PBMCs from NOD2 carriers produce collagen-high expressing cells, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. Enrichment of STAT3 regulation and gp130-ligands in activated fibroblasts and macrophages led us to reason that gp130 blockade might rescue the activated program. We correlate post-treatment induction of this pathway in anti-TNF non-responders and demonstrate in vivo amelioration of the activated myeloid-stromal niche, using a specific gp130 inhibitor, bazedoxifene. Our results demonstrate novel biological insights into NOD2-driven fibrosis in CD; gp130 blockade may benefit selected CD patients, potentially complementing anti-TNF therapy.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping