TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

Abstract

Chronic low grade inflammation is one of the major metabolic disorders in case of obesity and associated pathologies. By its important secretion function, the role of adipose tissue in this metabolic low grade inflammation is well known. Recently, it was demonstrated that the alarmin high mobility group box protein 1 (HMGB1) is involved in obesity-related pathologies by its increased serum levels in obese compared to normal weight individuals, and by its proinflammatory effects. However, the role of HMGB1 on adipocytes inflammation is poorly documented and we propose to investigate this point. Primary culture of human subcutaneous adipocytes were performed from human adipose tissue samples. Cells were treated with recombinant HMGB1 with/without anti-TLR4 antibody and inhibitors of NF-kB and P38 MAPK. Supernatants were collected for IL-6 and MCP-1 ELISA. HMGB1 initiates Toll-like receptor 4 (TLR4)-dependent activation of inflammation through the downstream NF-kB and P38 MAPK signaling pathway to upregulate the secretion of the pro-inflammatory cytokine IL-6. HMGB1 has proinflammatory effects on adipocytes. This reinforces the role of TLR4 in adipose tissue inflammation and antagonizing the HMGB1 inflammatory pathway could bring on new therapeutic targets to counteract obesity-associated pathologies.

High mobility group box‐1 induces pro‐inflammatory signaling in human nucleus pulposus cells via toll‐like receptor 4‐dependent pathway

“…Treatment of human NP cells with TLR4i completely mitigated HMGB1‐induced levels of IL‐6 and MMP‐1. Similar effects have been observed in epithelial cells, macrophages, adipocytes, and chondrocytes. We saw a partial (33%) and modest (<11.6%) inhibition in protein levels of pro‐inflammatory mediators with TLR‐2i and RAGEi, respectively.…”

“…18,19 Stimulation of these receptors has been shown to activate NF-kB pathway, which triggers the production of pro-inflammatory cytokines, such as IL-6 and MMP-1. 4,13,16,20 In IVD, an elevated IL-6 level decreases expression of ECM constituents, aggrecan and Collagen Type II, 2,21 and is associated with the progression of DD 22 and with LBP associated with DD. 23 MMP-1 levels have also been shown to be elevated in lumbar DD patients.…”

“…HMGB1 mediated inflammatory signaling occurs through a number of potential receptors, including toll‐like receptor (TLR)‐4, TLR‐2, and receptor for advanced glycation end products (RAGE) . Stimulation of these receptors has been shown to activate NF‐κB pathway, which triggers the production of pro‐inflammatory cytokines, such as IL‐6 and MMP‐1 . In IVD, an elevated IL‐6 level decreases expression of ECM constituents, aggrecan and Collagen Type II, and is associated with the progression of DD and with LBP associated with DD .…”

A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis

“…In the intracellular space, the RAGE ligands S100/calgranulins and HMGB1 (Taguchi et al, 2000; Hofmann et al, 1999) modulate calcium homeostasis and are nonhistone DNA binding proteins, respectively. In the extracellular space, these RAGE ligands assume response-to-stress functions, such as driving cellular inflammation through activation of nuclear factor-κB and p38 MAPK (Gunasekaran et al, 2016; Fujiya et al, 2014). Direct roles for the RAGE ligands in obesity have been demonstrated, as blocking antibodies to HMGB1 reduced obesity and inflammation in a mouse model (Montes etal., 2015).…”

“…This is not the case for Ager . However, the RAGE ligands HMGB1 and S100/calgranulins, such as S100A8/A9, may also bind TLRs (Gunasekaran et al, 2016; Hiratsuka et al, 2008). TLRs play innate roles in host defense, but the role of Ager in response to infectious pathogens is assuredly more complex (van Zoelen et al, 2011).…”