Pharmacological inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet.

Interleukin-6 (IL-6) is a major pro-inflammatory cytokine that demonstrates 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. Our recent studies identified a novel non-canonical signaling pathway that involves prolonged activation of SRC family of kinases (SFKs) by IL-6/gp130, where genetic or pharmacological inhibition of this pathway was protective in several acute injury models. This study was designed to assess the effect of a small molecule (R159) that inhibits the non-canonical signaling in a mouse model of multimorbidity induced by chronic inflammation. Aged mice were fed a high-fat diet (HFD) to exacerbate chronic inflammation and inflammaging-related conditions, and R159 significantly decreased systemic inflammatory responses in adipose tissue and liver. R159 was protective against trabecular bone and articular cartilage loss and markedly prevented neurogenesis decline. Moreover, R159 reduced weight gain induced by HFD and increased physical activity levels. These findings suggest that selective pharmacological inhibition of SFK signaling downstream of IL6/gp130 offers a promising strategy to alleviate systemic chronic inflammation and relevant multimorbidity.