Evidence of an anti-inflammatory toll-like receptor 9 (TLR 9) pathway in adipocytes

Abstract

Adipocytes express various pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and actively participate in anti-bacterial and anti-viral host defence. Obesity is associated with adipose tissue PRR expression. The potential role of Toll-like receptor 9 (TLR9) in adipocytes has not yet been investigated. Here, we evaluated TLR9 expression during adipocyte differentiation (AD) of 3T3-L1 adipocytes, in primary murine adipocytes and in different murine and human adipose tissue depots by real-time PCR, immunocytochemistry and immunohistochemistry. TLR9 expression was inhibited using specific siRNA-mediated knockdown, and TLR9 signaling was induced using specific class A, B and C agonistic CpG-oligodeoxynucleotide (ODN) treatment vs ODN controls in 3T3-L1 adipocytes and in primary murine adipocytes from Tlr9 wt/wt vs Tlr9 −/− mice. We found that TLR9 gene expression is induced during AD and that TLR9 protein is expressed in murine gonadal and human visceral adipocytes. AD depends on intact TLR9 expression. Tlr9 −/− mice demonstrate significantly reduced adiponectin serum levels, while siRNAmediated TLR9 knockdown led to reduced adiponectin mRNA expression in adipocytes. TLR9 ligands (CpG-ODNs) inhibit pro-inflammatory resistin secretion in mature 3T3-L1 adipocytes. Tlr9 −/− as compared to Tlr9 wt/wt adipocytes exhibit increased resistin and MCP1 secretion and reduced adiponectin secretion into cell culture supernatants, while TLR9 ligands (ODNs) show differential effects in Tlr9 −/− vs Tlr9 wt/wt primary murine adipocytes.

Toll-like receptor-mediated innate immunity against herpesviridae infection: a current perspective on viral infection signaling pathways

“…TLRs are mainly expressed on the membranes of immune cells including macrophages, dendritic cells, T cells, and B cells [17][18][19][20][21][22]. Moreover, TLRs are also found in non-immune cells, such as endothelial and epithelial cells, adipocytes, and cardiomyocytes [23][24][25][26][27]. TLRs predominantly occur on the cell surface, while TLRs 3, 7, 8, and 9 are expressed inside cells [3].…”

TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism

“…TLR9 upregulation in organs with relatively low basal levels is also observed in systems stressed with chronic obesity. TLR9 is significantly increased in visceral compared to subcutaneous adipose tissue in non-diabetic obese patients (84). It should be noted that most of the expression comes from the stromavascular cell fractions of the compartment (e.g., adipose tissue macrophages), not the adipocytes.…”

“…mtDNA is released by the stressed adipocytes as a damage-associated molecule pattern (DAMP), which not only exacerbates inflammation at the local tissue level but is released into the circulation. TLR9 expression increases in the visceral adipose tissue (84).…”

Toll-like receptors in the pathophysiology of obesity

“…Адипоцитарный TLR9 является предполагаемым новым защитным фактором при воспалении жировой ткани, сопровождающем ожирение [49]. Данный рецептор представлен в разнообразных иммунных клетках.…”