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The TNFSF12/TWEAK modulates colonic inflammatory fibroblast differentiation and promotes fibroblast-monocyte interactions

ABSTRACT: Fibroblasts acquire a pro-inflammatory phenotype in inflammatory bowel disease (IBD), but the factors driving this process and how fibroblasts contribute to the immune response is incompletely understood. The TNF superfamily factor 12 (TWEAK) has gained interest as a mediator of chronic inflammation. Here, we explore its role as a driver of inflammatory responses in fibroblasts and its contribution to fibroblast-monocyte interaction using human primary colonic fibroblasts, THP1 and peripheral blood mononuclear cells (PBMC). TWEAK induced the expression of cytokines, chemokines and immune receptors in fibroblasts. The TWEAK up-regulated transcriptome shared 29% homology with the previously published transcriptional profile of inflammatory fibroblasts from ulcerative colitis. TWEAK elevated surface expression of activated fibroblasts markers and adhesion molecules (PDPN, ICAM-1 and VCAM-1) and secretion of IL-6, CCL2 and CXCL10. In co-culture, fibroblasts induced monocyte adhesion and promoted a CD14high/ICAM-1 high phenotype in THP1 cells, both of which were enhanced when fibroblasts were pre-stimulated with TWEAK. Medium from TWEAK-treated fibroblast-THP1 co-cultures had elevated levels of CXCL1 and IL-8. PBMCs in co-culture with TWEAK-treated fibroblasts had altered surface expression of CCR2 and CD16, and increased CXCL1 and CXCL10. Our results indicate that TWEAK promotes and inflammatory fibroblast-monocyte crosstalk that may be amenable for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237845 | GEO | 2024/04/23

REPOSITORIES: GEO

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Project description:This SuperSeries is composed of the SubSeries listed below. Project abstract: In adult mammals, skin wound healing has evolved to favor rapid repair through the formation of fibrotic scar. These dermal scars are dysfunctional and may lead to chronic disfigurement and disability, yet the biologic mechanisms that drive fibrosis and prevent tissue regeneration remain unknown. Here, we report that reindeer (Rangifer tarandus) antler velvet exhibits regenerative wound healing, whereas identical full-thickness injury in dorsal back skin of the same animal forms fibrotic scar. This regenerative capacity is retained even following ectopic transplantation of velvet to a scar-forming site, demonstrating that this latent regenerative capacity is innate to velvet cells and independent of local factors derived from the growing antler. Single cell RNA-sequencing of uninjured skin revealed a marked divergence in resting fibroblast transcriptional states and immunomodulatory function. Uninjured velvet fibroblast shared a striking resemblance with human fetal fibroblasts whereas uninjured back skin fibroblasts exhibited an overrepresentation of pro-inflammatory genes resembling adult human fibroblasts. Identical skin injury resulted in site-specific fibroblast polarization; back fibroblasts exacerbated the inflammatory response, whereas velvet fibroblasts adopted an immunosuppressive state and reverted back to a regeneration-competent ground state. Consequently, velvet wounds exhibited an accelerated adoption of anti-inflammatory immune states and an expedited resolution of immune response. This study demonstrates reindeer as a novel comparative mammalian model to study both adult skin regeneration (velvet) and scar formation (back skin) within the same animal. Our study underscores the importance of fibroblast heterogeneity in shaping local immune cell functions that ultimately polarize wound healing outcomes. Purposeful, acute modulation of fibroblast-mediated immune signaling represents an important therapeutic avenue to mitigate scar and improve wound healing.

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The TNFSF12/TWEAK modulates colonic inflammatory fibroblast differentiation and promotes fibroblast-monocyte interactions

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