HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity

Abstract

Obesity has emerged as an imminent global public health concern over the past several decades. It has now become evident that obesity is characterized by the persistent and low-grade inflammation in the adipose tissue, and serves as an independent risk factor for many metabolic disorders such as diabetes and cardiovascular disease. Particularly, adipocytes originated from obese mice and humans likely predominate necrosis upon stressful insults, leading to passive release of cellular contents including the high mobility group box 1 (HMGB1) into the extracellular milieu. Extracellular HMGB1 acts as an innate alarmin to stimulate the activation of resident immune cells in the adipose tissue. Upon activation, those resident immune cells actively secrete additional HMGB1, which in turn activates/recruits additional immune cells, and induces adipocyte death. This review summarizes those novel discoveries in terms of HMGB1 in the initiation and maintenance of chronic inflammatory state in adipose tissue in obesity, and discusses its potential application in clinical settings.

HMGB1: A Possible Crucial Therapeutic Target for COVID-19?

“…HMGB1 has been extensively studied within the field of endocrinology as it is clearly involved with obesity [7], insulin resistance, and diabetes [8], and more recently polycystic ovary disease [9], another condition characterized by low-grade chronic inflammation ( Fig. 1b).…”

Role of the DNA repair genesH2AXandHMGB1in human fat distribution and lipid profiles

“…HMGB1 contains of two HMG-domains and one acidic tail, while post-translational modifications on the HMG domains are critical for cellular location and hence function of the HMGB1 protein 10. When the cysteine within HMG domain one is fully reduced, HMGB1 is located in the nucleus where it binds to DNA and unwound chromatin by replacing linker histone 1 (H1) 11 12. HMGB1 is hypothesized to enable repair proteins to bind around the damage site 12.…”

“…There is no doubt that HMGB1 is an important regulator of DNA repair while the precise mechanism is still under debate 14. However, HMGB1 can be actively secreted into the periphery, while dying adipocytes as well as macrophages serve as the main sources of circulating HMGB1 11. Extracellularly, HMGB1 acts in a proinflammatory manner for instance by promoting M2 to M1 macrophage polarization in adipose tissue 11.…”

“…However, HMGB1 can be actively secreted into the periphery, while dying adipocytes as well as macrophages serve as the main sources of circulating HMGB1 11. Extracellularly, HMGB1 acts in a proinflammatory manner for instance by promoting M2 to M1 macrophage polarization in adipose tissue 11. It is well demonstrated that cytoplasmic HMGB1 is more abundant in adipose tissue from obese humans compared with lean especially in visceral adipose cells including adipose stem cells but also stromal cells 11.…”

“…Extracellularly, HMGB1 acts in a proinflammatory manner for instance by promoting M2 to M1 macrophage polarization in adipose tissue 11. It is well demonstrated that cytoplasmic HMGB1 is more abundant in adipose tissue from obese humans compared with lean especially in visceral adipose cells including adipose stem cells but also stromal cells 11. Taken together, HMGB1 acts intracellularly to drive DNA repair.…”