Small fragments of hyaluronan are increased in individuals with obesity and contribute to low-grade inflammation through TLR-mediated activation of innate immune cells

Abstract

Background and aim Extracellular matrix (ECM) components released during excessive fat mass expansion are considered potential endogenous danger/alarm signals contributing to innate immune system activation. The aim of the current study was to specifically measure plasma levels of low molecular weight (LMW) hyaluronan (HA) and to evaluate its role as pro-inflammatory damage-associated molecular pattern (DAMP) on leukocyte response in the context of human obesity. Subjects and methods Participants were selected according to their body mass index (BMI, kg/m2) as non-obese (BMI < 29.9, n = 18) and obese (BMI > 29.9, n = 33). Plasma samples were size-dependent fractionated using ion-exchange chromatography to specifically obtain LMW HA fractions that were subsequently quantified by ELISA. Cell incubation experiments with synthetic HA molecules were performed on freshly Ficoll-isolated neutrophils (PMN) and peripheral blood monocytes (PBMC). Leukocyte and adipose tissue gene expression was assessed by real-time PCR and NF-κB activation by western blot. Plasma cytokine levels were measured by fluorescent bead-based (Luminex) immunoassay. Results We observed a statistically significant increase in the circulating levels of HA fragments of LMW in individuals with obesity which were consistent with significant up-regulated expression of the LMW HA synthesizing enzyme hyaluronan synthase-1 (HAS-1) in obese adipose tissue. Gene expression assessment of HA receptors revealed up-regulated levels for TLR2 in both obese PMN and PBMC. Synthetic HA molecules of different sizes were tested on leukocytes from healthy donors. LMW HA fragments (15–40 kDa) and not those from intermediate molecular sizes (75–350 kDa) induced a significant up-regulation of the expression of major pro-inflammatory cytokines such as IL-1β, MCP-1 and IL-8 in PBMC. Importantly, LMW HA was able to induce the phosphorylation of IKK α/β complex supporting its pro-inflammatory role through NF-κB activation. Conclusion Circulating LMW HA molecules are elevated in obesity and may play an important role in triggering low-grade inflammation and the development of metabolic complications.

The Related Metabolic Diseases and Treatments of Obesity

“…The expression of low molecular weight (15–40 kDa) hyaluronan (HA) molecules is upregulated in the circulating blood of obese individuals, which causes an increased expression of pro-inflammatory cytokines such as IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1, or CCL2) in peripheral blood monocytes [ 61 ]. The underlying molecular mechanism study shows that those HAs induce the activation of nuclear factor kappa B (NF-κB) signaling, by regulating the phosphorylation of the α/β complex IκB kinase (IKK).…”

Pathophysiological and Therapeutic Roles of Fascial Hyaluronan in Obesity-Related Myofascial Disease

“…Increasing evidence points to the involvement of hyaluronan and its receptors in obesity-related adipocyte hyperplasia and hypertrophy and adipose tissue metabolism [ 81 ]. An enhanced expression of hyaluronan synthase-1 was demonstrated in adipose tissue from obese patients [ 82 ]. It has been suggested that adipocyte hypertrophy contributes to adipose tissue inflammation [ 83 ].…”

“…It has been suggested that adipocyte hypertrophy contributes to adipose tissue inflammation [ 83 ]. Adipose tissue hypertrophy during obesity-related weight gain severely destabilizes extracellular matrix homeostasis by modifying the local oxygen supply, which in turn triggers cellular stress events and inflammation [ 82 ]. A potential role of hyaluronan in adipogenesis in vivo has been demonstrated in mouse models of high-fat diet-induced obesity [ 79 , 84 , 85 , 86 , 87 ].…”

“…It was shown that while total plasma hyaluronan molecules remain unaltered, the circulating level of low-molecular-weight hyaluronan fragments is elevated in obesity and may play a key role via Toll-like receptor (TLR)-mediated activation of innate immune cells in activating low-grade inflammatory phenotypes and other metabolic complications [ 82 , 93 ]. The expression of hyaluronan receptors in leukocytes is altered in obesity, with consequent alterations in the inflammatory response of leucocytes to low-molecular-weight hyaluronan.…”

“…The expression of hyaluronan receptors in leukocytes is altered in obesity, with consequent alterations in the inflammatory response of leucocytes to low-molecular-weight hyaluronan. It was shown that low-molecular-weight hyaluronan induces nuclear factor kappa B (NF-κB)-dependent activation in peripheral blood monocytes and THP-1 monocytes, leading to an increase in pro-inflammatory markers [ 82 ]. Hyaluronan increases tumor necrosis factor-α (TNF-α), insulin-like growth factor-1 (IGF-1) mRNA transcript expression and protein synthesis, interleukin 1 beta (IL-1β), and interleukin 8 (IL-8) via a CD44-mediated mechanism and modulates cytokine-activated lymphocyte adhesion to the endothelium [ 94 , 95 ].…”