Pharmacological 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:
39732741
Funding Grants:
Public Summary:
Interleukin-6 (IL-6) is a molecule that helps control inflammation, and its levels rise with age and higher body weight, contributing to chronic inflammation and age-related diseases. Although IL-6 also has important roles in metabolism and tissue repair, blocking its harmful effects without disrupting its beneficial ones has been challenging. Recent research discovered a specific IL-6 signaling pathway that activates enzymes called SRC family kinases (SFKs), and blocking this pathway can protect against tissue damage.
In this study, researchers tested a new drug, R159, that blocks this harmful IL-6/SFK pathway. They gave the drug to older mice on a high-fat diet, which normally causes widespread inflammation and aging-related problems. The treatment significantly reduced inflammation in fat and liver tissue and protected the mice from bone loss, joint damage, and declines in brain cell regeneration. R159 also prevented excessive weight gain and boosted physical activity. These results suggest that selectively blocking this IL-6 signaling branch may be a promising way to reduce chronic inflammation and multiple age-related health issues.
Scientific Abstract:
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.
