Journal Article

Toll-like Receptors 1, 3 and 7 Activate Distinct Genetic Features of NF-κB Signaling and γ-Protocadherin Expression in Human Cardiac Fibroblasts

Mattsson Hultén, Lillemor, Chaudhari, Aditi, Axelsson, Camila, Rotter Sopasakis, Victoria

2025

Overview

Fibroblasts play a pivotal role in key processes within the heart, particularly in cardiac remodeling that follows both ischemic and non-ischemic injury. During remodeling, fibroblasts drive fibrosis and inflammation by reorganizing the extracellular matrix and modulating the immune response, including toll-like receptor (TLR) activation, to promote tissue stabilization. Building on findings from our prior research on heart tissue from patients with advanced coronary artery disease and aortic valve disease, this study sought to explore specific effects of TLR1, TLR3, and TLR7 activation on NF-κB signaling, proinflammatory cytokine production, and γ-protocadherin expression in cardiac fibroblasts. Human cardiac fibroblasts were exposed to agonists for TLR1, TLR3, or TLR7 for 24 h, followed by an analysis of NF-κB signaling, cytokine production, and γ-protocadherin expression. The activation of these TLRs triggered distinct responses in the NF-κB signaling pathway, with TLR3 showing a stronger activation profile compared to TLR1 and TLR7, particularly in downregulating γ-protocadherin expression. These findings highlight a potential role for TLR3 in amplifying inflammatory responses and reducing γ-protocadherin levels in cardiac fibroblasts, correlating with the enhanced inflammation and lower γ-protocadherin expression observed in diseased myocardium from patients with coronary artery disease and aortic valve disease. Consequently, TLR3 represents a potential therapeutic target for modulating immune responses in cardiovascular diseases.

• Publisher: Springer US,Springer Nature B.V
• Subject: Agonists / Aortic valve / Biomedical and Life Sciences / Biomedicine / Cadherins - biosynthesis / Cadherins - genetics / Cardiomyocytes / Cardiovascular diseases / Cardiovascular system / Cell Biology / Cell culture / Cellbiologi / Cells, Cultured / Communication / Coronary artery disease / Cytokines / Disease / Extracellular matrix / Fibroblasts / Fibroblasts - metabolism / Fibrosis / gamma-protocadherins / Gene expression / Growth factors / Heart / Heart disease / Heart diseases / Humans / Immune response / Immunology / Inflammation / Internal Medicine / Invoices / Ischemia / MicroRNAs / Myocardium / Myocardium - cytology / Myocardium - metabolism / NF-kappa B - metabolism / NF-kB signaling / NF-κB protein / Pathology / Pharmacology/Toxicology / Principal components analysis / Protocadherin / Rheumatic heart disease / Rheumatology / Signal transduction / Signal Transduction - physiology / Software / Therapeutic targets / TLR1 protein / TLR3 protein / TLR7 protein / Toll-Like Receptor 1 - agonists / Toll-Like Receptor 1 - metabolism / Toll-Like Receptor 3 - agonists / Toll-Like Receptor 3 - metabolism / Toll-Like Receptor 7 - agonists / Toll-Like Receptor 7 - metabolism / Toll-like receptors / Tumor necrosis factor-TNF