Inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet.
Publication Year:
2024
PubMed ID:
38645030
Funding Grants:
Public Summary:
Interleukin-6 (IL-6) is a molecule that helps regulate inflammation, metabolism, and tissue repair. Its levels rise with age and higher body weight, contributing to chronic inflammation and age-related health problems. In earlier work, researchers found that blocking one specific IL-6 signaling route—through a site called Y814 on the gp130 receptor—improves healing and reduces inflammation in mice. In this study, they tested whether blocking this pathway could also reduce the harmful effects of a high-fat diet, which is used to mimic accelerated aging.
Mice genetically engineered to block this pathway showed much less inflammation in their fat and liver tissue, and they were protected from bone loss and joint damage. Drugs that inhibit the same pathway produced similar benefits, including higher activity levels and protection against inflammation-related declines in brain cell growth. These results suggest that selectively blocking this branch of IL-6 signaling may help reduce chronic inflammation and multiple age-related diseases, even in the context of obesity.
Scientific Abstract:
Interleukin-6 (IL-6) is a major pro-inflammatory cytokine for which the levels in plasma demonstrate a robust correlation with age and body mass index (BMI) as part of the senescence-associated secretory phenotype. IL-6 cytokines also play a crucial role in metabolic homeostasis and regenerative processes, primarily via the canonical STAT3 pathway. Thus, selective modulation of IL-6 signaling may offer a unique opportunity for therapeutic interventions. Recently, we discovered that a non-canonical signaling pathway downstream of tyrosine (Y) 814 within the intracellular domain of gp130, the IL-6 co-receptor, is responsible for the recruitment and activation of SRC family of kinases (SFK). Mice with constitutive genetic inactivation of gp130 Y814 (F814 mice) show accelerated resolution of inflammatory response and superior regenerative outcomes in skin wound healing and posttraumatic models of osteoarthritis. The current study was designed to explore if selective genetic or pharmacological inhibition of the non-canonical gp130-Y814/SFK signaling reduces systemic chronic inflammation and multimorbidity in a high-fat diet (HFD)-induced model of accelerated aging. F814 mice showed significantly reduced inflammatory response to HFD in adipose and liver tissue, with significantly reduced levels of systemic inflammation compared to wild type mice. F814 mice were also protected from HFD-induced bone loss and cartilage degeneration. Pharmacological inhibition of gp130-Y814/SFK in mice on HFD mirrored the effects observed in F814 mice on HFD; furthermore, this pharmacological treatment also demonstrated a marked increase in physical activity levels and protective effects against inflammation-associated suppression of neurogenesis in the brain tissue compared to the control group. These findings suggest that selective inhibition of SFK signaling downstream of gp130 receptor represents a promising strategy to alleviate systemic chronic inflammation. Increased degenerative changes and tissue senescence are inevitable in obese and aged organisms, but we demonstrated that the systemic response and inflammation-associated multi-morbidity can be therapeutically mitigated.
