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
-
- Indoles/pharmacology
- Macrophages/cytology
- Macrophages/metabolism
- Humans
- STAT3 Transcription Factor/metabolism
- Animals
- Cytokine Receptor gp130/antagonists & inhibitors
- Cytokine Receptor gp130/metabolism*
- Ileitis/metabolism
- WT1 Proteins/metabolism
- Collagen/metabolism
- Alleles
- Disease Models, Animal
- Zebrafish Proteins/metabolism
- Lipopolysaccharide Receptors/metabolism
- Myeloid Cells/cytology*
- Myeloid Cells/metabolism
- Interleukin-11/metabolism
- Fibroblasts/cytology
- Fibroblasts/metabolism
- Receptor, Platelet-Derived Growth Factor alpha/metabolism
- Crohn Disease/metabolism*
- Zebrafish
- Stromal Cells/cytology*
- Stromal Cells/metabolism
- Nod2 Signaling Adaptor Protein/metabolism*
- Female
- Male
- PubMed
- 33789339 Full text @ Nature
Citation
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. (2021) A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease. Nature. 593(7858):275-281.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping