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Mononuclear Phagocyte Differentiation Highlights the Role of NOD2 in Stricturing Crohn's Disease, Revealing New Therapeutic Targets.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Mononuclear Phagocyte Differentiation Highlights the Role of NOD2 in Stricturing Crohn's Disease, Revealing New Therapeutic Targets./
Author:	Nayar, Shikha.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	132 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-12, Section: B.
Contained By:	Dissertations Abstracts International82-12B.
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28540142
ISBN:	9798738635854

Mononuclear Phagocyte Differentiation Highlights the Role of NOD2 in Stricturing Crohn's Disease, Revealing New Therapeutic Targets.
Nayar, Shikha.

Mononuclear Phagocyte Differentiation Highlights the Role of NOD2 in Stricturing Crohn's Disease, Revealing New Therapeutic Targets. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 132 p.

Source: Dissertations Abstracts International, Volume: 82-12, Section: B.

Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2021.

This item must not be sold to any third party vendors.

Crohn's disease (CD) is a chronic inflammatory intestinal disease, with frequent aberrant healing and fibrostenotic complications. Increasingly, single-cell technologies have elucidated key cell subpopulations and secreted mediators that contribute to disease pathogenesis, and to treatment non-response. Crosstalk between activated myeloid and stromal cells is critical in pathogenicity with increases in intravasating monocytes correlated to anti-TNF treatment non-response. The highest effect risk alleles are loss-of-function mutations in NOD2, which increase risk for a CD fibrostenotic phenotype, stricturing. However, biological mechanisms underlying the pathogenesis of NOD2-driven stricturing remain largely uncharacterized. Here we show that loss of NOD2 function leads to dysregulated activated fibroblast and macrophage homeostasis via direct ex vivo analyses of patients carrying NOD2 risk alleles. In vitro validation reveals that CD14+PBMCs from NOD2 carriers produce collagen-high expressing cells when differentiated, elevating production of transcripts involved in the activated program. We develop and utilize novel zebrafish models of intestinal injury in the context of nod2 deficiency and reveal elevation of conserved pathogenic signatures in vivo. Single-cell transcriptomic and phenotypic analyses enabled us to precisely define timing and progression of aberrant injury and repair. 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, involving gp130 blockade by a specific inhibitor, bazedoxifene. Overall, our results demonstrate novel biological insights into NOD2-driven fibrotic complications in CD; gp130 blockade may benefit selected CD patients, potentially complementing anti-TNF therapy.

ISBN: 9798738635854Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Crohn's

Mononuclear Phagocyte Differentiation Highlights the Role of NOD2 in Stricturing Crohn's Disease, Revealing New Therapeutic Targets.
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520 $a Crohn's disease (CD) is a chronic inflammatory intestinal disease, with frequent aberrant healing and fibrostenotic complications. Increasingly, single-cell technologies have elucidated key cell subpopulations and secreted mediators that contribute to disease pathogenesis, and to treatment non-response. Crosstalk between activated myeloid and stromal cells is critical in pathogenicity with increases in intravasating monocytes correlated to anti-TNF treatment non-response. The highest effect risk alleles are loss-of-function mutations in NOD2, which increase risk for a CD fibrostenotic phenotype, stricturing. However, biological mechanisms underlying the pathogenesis of NOD2-driven stricturing remain largely uncharacterized. Here we show that loss of NOD2 function leads to dysregulated activated fibroblast and macrophage homeostasis via direct ex vivo analyses of patients carrying NOD2 risk alleles. In vitro validation reveals that CD14+PBMCs from NOD2 carriers produce collagen-high expressing cells when differentiated, elevating production of transcripts involved in the activated program. We develop and utilize novel zebrafish models of intestinal injury in the context of nod2 deficiency and reveal elevation of conserved pathogenic signatures in vivo. Single-cell transcriptomic and phenotypic analyses enabled us to precisely define timing and progression of aberrant injury and repair. 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, involving gp130 blockade by a specific inhibitor, bazedoxifene. Overall, our results demonstrate novel biological insights into NOD2-driven fibrotic complications in CD; gp130 blockade may benefit selected CD patients, potentially complementing anti-TNF therapy.
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