IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts

Recent studies show a connection between glycolysis and inflammatory response in rheumatoid arthritis (RA) macrophages (M phi s) and fibroblasts (FLS). Yet, it is unclear which pathways could be targeted to rebalance RA M phi s and FLS metabolic reprogramming. To identify novel targets that could normalize RA metabolic reprogramming, TLR7-mediated immunometabolism was characterized in RA M phi s, FLS and experimental arthritis. We uncovered that GLUT1, HIF1 alpha, cMYC, LDHA and lactate were responsible for the TLR7-potentiated metabolic rewiring in RA M phi s and FLS, which was negated by IRAK4i. While in RA FLS, HK2 was uniquely expanded by TLR7 and negated by IRAK4i. Conversely, TLR7-driven hypermetabolism, non-oxidative PPP (CARKL) and oxidative phosphorylation (PPAR gamma) were narrowly dysregulated in TLR7-activated RA M phi s and FLS and was reversed by IRAK4i. Consistently, IRAK4i therapy disrupted arthritis mediated by miR-Let7b/TLR7 along with impairing a broad-range of glycolytic intermediates, GLUT1, HIF1 alpha, cMYC, HK2, PFKFB3, PKM2, PDK1 and RAPTOR. Notably, inhibition of the mutually upregulated glycolytic metabolites, HIF1 alpha and cMYC, was capable of mitigating TLR7-induced inflammatory imprint in RA M phi s and FLS. In keeping with IRAK4i, treatment with HIF1i and cMYCi intercepted TLR7-enhanced IRF5 and IRF7 in RA M phi s, distinct from RA FLS. Interestingly, in RA M phi s and FLS, IRAK4i counteracted TLR7-induced CARKL reduction in line with HIF1i. Whereas, cMYCi in concordance with IRAK4i, overturned oxidative phosphorylation via PPAR gamma in TLR7-activated RA M phi s and FLS. The blockade of IRAK4 and its interconnected intermediates can rebalance the metabolic malfunction by obstructing glycolytic and inflammatory phenotypes in RA M phi s and FLS.

Automated summary

"Recent studies have shown a connection between glycolysis and inflammatory response in rheumatoid arthritis (RA) macrophages (M phi s) and fibroblasts (FLS). Targeting specific pathways, such as IRAK4i, can potentially rebalance the metabolic dysfunction in RA cells while modulating TLR7-mediated immunometabolism."