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TNFα Priming of Human Pericytes Enhances TGFβ1-Smad Signaling and Microvascular Fibrotic Activation Via and Increase in TGFβRII Activity

ABSTRACT: Effective anti-fibrotic treatments remain elusive, as current drugs do not reverse fibrotic progression. A deeper understanding of how understudied contributor cells, such as pericytes, intersect with inflammatory and fibrotic cues is needed to uncover mechanisms driving fibrosis. We hypothesize that pro-inflammatory tumor necrosis factor-α (TNFα) can modulate transforming growth factor- β1 (TGFβ1) signaling in a time dependent manner in human pericytes via an increase in TGFβRII activity. Pericytes were subject to either Priming (4 hours of TNFα treatment followed by TGFβ1 treatment) or Coactivation (TNFα and TGFβ1 simultaneous treatment) to assess the role of TNFα activity on TGFβ1, resulting in distinct genetic profiles and ultimately differences in downstream pSmad2 activation, collagen deposition, MMP secretion and cellular contraction. Altogether, these findings provide evidence that the timing of TNFα exposure shapes its influence on TGFβ1-mediated fibrotic signaling in pericytes, at times exacerbating and at times attenuating pericyte fibrotic responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312074 | GEO | 2026/10/01

REPOSITORIES: GEO

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Project description:Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive fibroblast-to-myofibroblast transition (FMT) and extracellular matrix (ECM) deposition, largely driven by transforming growth factor-beta 1 (TGFβ1). Existing therapies offer limited efficacy, particularly in advanced disease. Circadian rhythms have recently emerged as key modulators of lung inflammation and fibrosis. In this study, we developed an in vitro model of chronic fibrotic signaling using adenovirus-mediated TGFβ1 overexpression (Ad-TGFβ1) or human recombinant protein TGFβ1 in primary human lung fibroblasts. Using this model, we investigated the antifibrotic potential of STL1267, a next-generation Rev-erbα agonist with improved potency, specificity, and pharmacokinetic properties. RNA sequencing and pathway analysis revealed that STL1267 significantly reversed Ad-TGFβ1-induced expression of genes associated with ECM remodeling, collagen biosynthesis, and immune suppression. STL1267 also upregulated pathways related to IL-10, IL-4, and IL-13 signaling, which are known to counteract fibrotic responses. Quantitative PCR and immunoblotting confirmed STL1267's ability to downregulate key pro-fibrotic markers, including COL1A1, αSMA, FN1, and FAP, at both gene and protein levels. Comparative studies with other Rev-erbα agonists (GSK4112, SR9009), Saracatinib, and FDA-approved antifibrotic drugs (Pirfenidone, Nintedanib) demonstrated superior efficacy of STL1267 in inhibiting both preventive and post-fibrotic induction models. Moreover, lentiviral overexpression of Rev-erbα suppressed TGFβ1-induced αSMA expression, supporting a direct antifibrotic role. These findings highlight Rev-erbα as a key regulator of myofibroblast differentiation and support both STL1267 and GSK4112 as promising candidates for circadian-based antifibrotic therapy. Future in vivo studies are warranted to evaluate its translational potential in idiopathic pulmonary fibrosis.

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TNFα Priming of Human Pericytes Enhances TGFβ1-Smad Signaling and Microvascular Fibrotic Activation Via and Increase in TGFβRII Activity

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