Dual and context-dependent role of the interleukin-33/soluble suppression of tumorigenicity 2 axis in obesity and adipose tissue inflammation

Obesity is increasingly recognized as a state of chronic, unresolved inflammation in which the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis may represent a key immunometabolic regulator. We investigated circulating concentrations and adipose tissue expression levels of IL-33 and its soluble receptor sST2 in obesity and type 2 diabetes, and evaluated their functional effects on adipocytes and macrophages. Circulating IL-33 levels were significantly elevated (P < 0.01) in obesity compared with controls, being positively (P < 0.01) correlated with body mass index and HOMA-IR and negatively (P < 0.05) with HDL cholesterol. Conversely, sST2 was reduced in obesity (P < 0.05) and inversely associated with body fat percentage (P < 0.001) and fibrinogen levels (P < 0.05), suggesting enhanced IL-33 bioavailability. Visceral adipose tissue (VAT) from subjects with obesity exhibited increased IL-33 gene and protein expression levels (P < 0.01, for both). Functional analyses show that IL-33 induced (P < 0.01) the expression of adiponectin, omentin (ITLN1), and IL13 in adipocytes and attenuated (P < 0.01) LPS-driven IL1B and TNF expression. In macrophages, adipocyte-conditioned medium (ACM) from people with obesity strongly suppressed (P < 0.01) IL33 expression, while exogenous IL-33 counteracted pro-inflammatory activation, reducing LPS- and ACM-induced IL1B, IL6, and IL8 (all P < 0.01). Our findings indicate a dual and a context-dependent role of IL-33 in obesity, while elevated circulating and VAT IL-33 associate with adiposity and metabolic dysfunction, IL-33 may also exert protective effects by dampening macrophage inflammation and promoting anti-inflammatory adipokines.