PROJECT ID: GSE150498

Data source GEO: GSE150498
Description Crohn’s disease (CD) is a chronic inflammatory intestinal disease, often characterized by aberrant healing and stricturing complications. Mechanisms underlying NOD2-pathogenicity and salvage pathways in anti-TNF and refractory patients remain largely uncharacterized. Here we show that loss of NOD2 function leads to aberrant activated fibroblast and macrophage homeostasis through the upregulation of a pathogenic signature, and propose new precision therapeutic approaches involving gp130 blockade for select CD patients, to potentially supplement anti-TNF therapy
Key word Crohn's disease; NOD2 deficiency; gp130 blockade; fibroblasts; macrophages; STAT3 pathway
Publication Nayar S, Morrison JK, Giri M, Gettler K et al. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease. Nature 2021 May;593(7858):275-281. PMID: 33789339
Abstract NOD2 deficiency drives fibrosis and stricturing complications in Crohn's disease through dysregulated homeostasis of activated fibroblasts and macrophages, which is ameliorated by gp130 blockade in human cell and zebrafish models. 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 disease, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD2, which increase the risk of stricturing. 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.


Dataset Information

Dataset ID Species Tissue / Organ Experiment type Sample Source dataset ID
1. GSE150498 (untreated ctrl) Danio rerio intestine baseline 6dpf, untreated ctrl GEO: GSM4551415
2. GSE150498 (DSS treated) Danio rerio intestine disease 6dpf, DSS treated GEO: GSM4551416
3. GSE150498 (wildtype, untreated) Danio rerio intestine baseline 6dpf, wildtype, untreated GEO: GSM4878622
4. GSE150498 (nod2-|-, untreated) Danio rerio intestine disease 6dpf, nod2-/-, untreated GEO: GSM4878623
5. GSE150498 (wildtype, 1X DSS) Danio rerio intestine disease 6dpf, wildtype, 1X DSS GEO: GSM4878624
6. GSE150498 (nod2-|-, 1X DSS) Danio rerio intestine disease 6dpf, nod2-/-, 1X DSS GEO: GSM4878625
7. GSE150498 (wildtype, 2X DSS) Danio rerio intestine disease 6dpf, wildtype, 2X DSS GEO: GSM4878627
8. GSE150498 (wildtype, 2X DSS+BZA) Danio rerio intestine disease 6dpf, wildtype, 2X DSS+BZA GEO: GSM4878628
9. GSE150498 (nod2-|-, 2X DSS) Danio rerio intestine disease 6dpf, nod2-/-, 2X DSS GEO: GSM4878630
10. GSE150498 (nod2-|-, 2X DSS+BZA) Danio rerio intestine disease 6dpf, nod2-/-, 2X DSS+BZA GEO: GSM4878631

Clustering Result

Cluster Cell type Gene id (symbol) Marker class Evidence
2 Chondrocytes ENSDARG00000093381 (tgm2l) marker DOI:10.1038/s41586-021-03484-5
2 Chondrocytes ENSDARG00000059391 (gyg1b) marker DOI:10.1038/s41586-021-03484-5
3 Smooth muscle cells ENSDARG00000030980 (csrp1b) marker DOI:10.1038/s41586-021-03484-5
3 Smooth muscle cells ENSDARG00000086391 (cald1b) marker DOI:10.1038/s41586-021-03484-5
4 Enterocytes ENSDARG00000012076 (apoa1a) marker DOI:10.1038/s41586-021-03484-5
5 Epithelial cells ENSDARG00000016691 (cd9b) marker DOI:10.1038/s41586-021-03484-5
6 Epithelial cells ENSDARG00000104314 (nrg1) marker DOI:10.1038/s41586-021-03484-5
8 Epithelial cells ENSDARG00000079302 (and2) marker DOI:10.1038/s41586-021-03484-5
9 Hepatocytes ENSDARG00000043719 (c3a.6) marker DOI:10.1038/s41586-021-03484-5
10 Endothelium ENSDARG00000105215 (kdrl) marker DOI:10.1038/s41586-021-03484-5
11 Epithelial cells ENSDARG00000092947 (cyt1) marker DOI:10.1038/s41586-021-03484-5
13 Enteric neuron ENSDARG00000099744 (gap43) marker DOI:10.1038/s41586-021-03484-5
15 Pancreatic cells ENSDARG00000018263 (pdia2) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
1 Enterocytes ENSDARG00000012076 (apoa1a) marker DOI:10.1038/s41586-021-03484-5
2 Enterocytes ENSDARG00000012076 (apoa1a) marker DOI:10.1038/s41586-021-03484-5
3 Mesenchymal cells ENSDARG00000093303 (ifitm1) marker DOI:10.1038/s41586-021-03484-5
4 Epithelial cells ENSDARG00000040534 (epcam) marker DOI:10.1038/s41586-021-03484-5
5 Smooth muscle cells ENSDARG00000030980 (csrp1b) marker DOI:10.1038/s41586-021-03484-5
5 Smooth muscle cells ENSDARG00000086391 (cald1b) marker DOI:10.1038/s41586-021-03484-5
6 Pancreatic cells ENSDARG00000018263 (pdia2) marker DOI:10.1038/s41586-021-03484-5
7 Endothelium ENSDARG00000105215 (kdrl) marker DOI:10.1038/s41586-021-03484-5
9 Hepatocytes ENSDARG00000043719 (c3a.6) marker DOI:10.1038/s41586-021-03484-5
12 Epithelial cells ENSDARG00000079302 (and2) marker DOI:10.1038/s41586-021-03484-5
13 Chondrocytes ENSDARG00000073699 (col9a1a) marker DOI:10.1038/s41586-021-03484-5
13 Chondrocytes ENSDARG00000093381 (tgm2l) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
2 Mesenchymal cells ENSDARG00000093303 (ifitm1) marker DOI:10.1038/s41586-021-03484-5
4 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5
5 Corpuscles of stannius ENSDARG00000055395 (foxq1b) marker DOI:10.1038/s41586-021-03484-5
6 Smooth muscle cells ENSDARG00000030980 (csrp1b) marker DOI:10.1038/s41586-021-03484-5
6 Smooth muscle cells ENSDARG00000086391 (cald1b) marker DOI:10.1038/s41586-021-03484-5
7 Squamous epithelial ENSDARG00000014488 (ca2) marker DOI:10.1038/s41586-021-03484-5
8 Brush border cells ENSDARG00000103342 (wu:fa56d06) marker DOI:10.1038/s41586-021-03484-5
9 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
2 Mesenchymal cells ENSDARG00000093303 (ifitm1) marker DOI:10.1038/s41586-021-03484-5
4 Brush border cells ENSDARG00000023151 (ucp1) marker DOI:10.1038/s41586-021-03484-5
5 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5
6 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5
7 Squamous epithelial ENSDARG00000014488 (ca2) marker DOI:10.1038/s41586-021-03484-5
8 Corpuscles of stannius ENSDARG00000055395 (foxq1b) marker DOI:10.1038/s41586-021-03484-5
9 Stromal ENSDARG00000034588 (scn4ab) marker DOI:10.1038/s41586-021-03484-5
10 Endothelium ENSDARG00000014059 (cldn5b) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
2 Brush border cells ENSDARG00000103342 (wu:fa56d06) marker DOI:10.1038/s41586-021-03484-5
3 Smooth muscle cells ENSDARG00000030980 (csrp1b) marker DOI:10.1038/s41586-021-03484-5
3 Smooth muscle cells ENSDARG00000086391 (cald1b) marker DOI:10.1038/s41586-021-03484-5
4 Epithelial cells ENSDARG00000016691 (cd9b) marker DOI:10.1038/s41586-021-03484-5
5 Squamous epithelial ENSDARG00000014488 (ca2) marker DOI:10.1038/s41586-021-03484-5
6 Enteroendocrine -- (zgc:153845) marker DOI:10.1038/s41586-021-03484-5
7 Chondrocytes ENSDARG00000073699 (col9a1a) marker DOI:10.1038/s41586-021-03484-5
7 Chondrocytes ENSDARG00000093381 (tgm2l) marker DOI:10.1038/s41586-021-03484-5
7 Chondrocytes ENSDARG00000059391 (gyg1b) marker DOI:10.1038/s41586-021-03484-5
8 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5
9 Fibroblasts ENSDARG00000093572 (lamc3) marker DOI:10.1038/s41586-021-03484-5
10 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5
11 Stromal ENSDARG00000013266 (colec11) marker DOI:10.1038/s41586-021-03484-5
12 Stromal ENSDARG00000034588 (scn4ab) marker DOI:10.1038/s41586-021-03484-5
14 Endothelium ENSDARG00000060263 (pecam1) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
1 Mesenchymal cells ENSDARG00000093303 (ifitm1) marker DOI:10.1038/s41586-021-03484-5
2 Enterocytes ENSDARG00000012076 (apoa1a) marker DOI:10.1038/s41586-021-03484-5
3 Ionocytes ENSDARG00000060622 (si:ch73-14h1.2) marker DOI:10.1038/s41586-021-03484-5
4 Epithelial cells ENSDARG00000040045 (cldn1) marker DOI:10.1038/s41586-021-03484-5
5 Enteroendocrine -- (zgc:153845) marker DOI:10.1038/s41586-021-03484-5
6 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5
7 Smooth muscle cells ENSDARG00000030980 (csrp1b) marker DOI:10.1038/s41586-021-03484-5
7 Smooth muscle cells ENSDARG00000086391 (cald1b) marker DOI:10.1038/s41586-021-03484-5
8 Epithelial cells ENSDARG00000097725 (si:dkey-96g2.1) marker DOI:10.1038/s41586-021-03484-5
9 Epithelial cells ENSDARG00000043128 (cldne) marker DOI:10.1038/s41586-021-03484-5
10 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5
11 Hepatocytes ENSDARG00000102456 (cfhl4) marker DOI:10.1038/s41586-021-03484-5
12 Squamous epithelial ENSDARG00000014488 (ca2) marker DOI:10.1038/s41586-021-03484-5
13 Stromal ENSDARG00000034588 (scn4ab) marker DOI:10.1038/s41586-021-03484-5
14 Endothelium ENSDARG00000105215 (kdrl) marker DOI:10.1038/s41586-021-03484-5
15 Chondrocytes ENSDARG00000093381 (tgm2l) marker DOI:10.1038/s41586-021-03484-5
15 Chondrocytes ENSDARG00000059391 (gyg1b) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
1 Enterocytes ENSDARG00000012076 (apoa1a) marker DOI:10.1038/s41586-021-03484-5
2 Epithelial cells ENSDARG00000016691 (cd9b) marker DOI:10.1038/s41586-021-03484-5
4 Enteroendocrine -- (zgc:153845) marker DOI:10.1038/s41586-021-03484-5
5 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5
6 Smooth muscle cells ENSDARG00000030980 (csrp1b) marker DOI:10.1038/s41586-021-03484-5
6 Smooth muscle cells ENSDARG00000086391 (cald1b) marker DOI:10.1038/s41586-021-03484-5
7 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5
8 Stromal ENSDARG00000013266 (colec11) marker DOI:10.1038/s41586-021-03484-5
9 Pancreatic cells ENSDARG00000018263 (pdia2) marker DOI:10.1038/s41586-021-03484-5
10 Enteric neuron ENSDARG00000014420 (elavl3) marker DOI:10.1038/s41586-021-03484-5
10 Enteric neuron ENSDARG00000021143 (rtn1b) marker DOI:10.1038/s41586-021-03484-5
11 Chondrocytes ENSDARG00000059391 (gyg1b) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
3 Brush border cells ENSDARG00000023151 (ucp1) marker DOI:10.1038/s41586-021-03484-5
4 Enteroendocrine -- (zgc:153845) marker DOI:10.1038/s41586-021-03484-5
5 Smooth muscle cells ENSDARG00000030980 (csrp1b) marker DOI:10.1038/s41586-021-03484-5
5 Smooth muscle cells ENSDARG00000086391 (cald1b) marker DOI:10.1038/s41586-021-03484-5
6 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5
7 Epithelial cells -- (wu:fj19g03) marker DOI:10.1038/s41586-021-03484-5
8 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
1 Mesenchymal cells ENSDARG00000093303 (ifitm1) marker DOI:10.1038/s41586-021-03484-5
2 Brush border cells ENSDARG00000103342 (wu:fa56d06) marker DOI:10.1038/s41586-021-03484-5
3 Squamous epithelial ENSDARG00000014488 (ca2) marker DOI:10.1038/s41586-021-03484-5
4 Chondrocytes ENSDARG00000093381 (tgm2l) marker DOI:10.1038/s41586-021-03484-5
4 Chondrocytes ENSDARG00000059391 (gyg1b) marker DOI:10.1038/s41586-021-03484-5
5 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5
6 Enteroendocrine -- (zgc:153845) marker DOI:10.1038/s41586-021-03484-5
7 Fibroblasts ENSDARG00000044935 (hpdb) marker DOI:10.1038/s41586-021-03484-5
8 Epithelial cells ENSDARG00000092947 (cyt1) marker DOI:10.1038/s41586-021-03484-5
9 Pancreatic cells ENSDARG00000018263 (pdia2) marker DOI:10.1038/s41586-021-03484-5
10 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5
11 Stromal ENSDARG00000013266 (colec11) marker DOI:10.1038/s41586-021-03484-5
12 Endothelium ENSDARG00000105215 (kdrl) marker DOI:10.1038/s41586-021-03484-5
12 Endothelium ENSDARG00000014059 (cldn5b) marker DOI:10.1038/s41586-021-03484-5
14 Enteric neuron ENSDARG00000021143 (rtn1b) marker DOI:10.1038/s41586-021-03484-5

Cluster Cell type Gene id (symbol) Marker class Evidence
3 Brush border cells ENSDARG00000103342 (wu:fa56d06) marker DOI:10.1038/s41586-021-03484-5
4 Mesenchymal cells ENSDARG00000093303 (ifitm1) marker DOI:10.1038/s41586-021-03484-5
5 Epithelial cells ENSDARG00000016691 (cd9b) marker DOI:10.1038/s41586-021-03484-5
6 Proliferative myeloid + ILC ENSDARG00000026350 (wasb) marker DOI:10.1038/s41586-021-03484-5
8 Pancreatic cells ENSDARG00000018263 (pdia2) marker DOI:10.1038/s41586-021-03484-5
9 Hepatocytes ENSDARG00000102456 (cfhl4) marker DOI:10.1038/s41586-021-03484-5
10 Enteroendocrine + ILC3 ENSDARG00000004015 (adcyap1a) marker DOI:10.1038/s41586-021-03484-5
11 Endothelium ENSDARG00000105215 (kdrl) marker DOI:10.1038/s41586-021-03484-5
12 Epithelial cells ENSDARG00000097725 (si:dkey-96g2.1) marker DOI:10.1038/s41586-021-03484-5