SDH inhibition quenches rheumatoid arthritis flare-associated IL-1β+IFN-γ+ macrophages via NF-κB/STAT4

Scritto il 04/09/2026

da Stephanie R Zack

CONCLUSIONS: SDH functions as a metabolic-immune checkpoint in pathogenic IL-1β^(+)NFKB1^(+)IFN-γ^(+)STAT4^(lo) MΦs in RA. Targeting SDH may concurrently resolve mitochondrial dysfunction and inflammation in patients experiencing disease flares, with synovial enrichment of TLR5, SDH, IL-1β, NFKB1, and IFN-γ serving as predictive biomarkers.

Ann Rheum Dis. 2026 Sep 4:S0003-4967(26)00483-8. doi: 10.1016/j.ard.2026.07.025. Online ahead of print.

ABSTRACT

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease in which distinct macrophage (MΦ) endotypes can guide therapy. TLR5, upregulated during disease flares, drives an IL-1β⁺NFKB1⁺IFN-γ⁺STAT4^lo MΦ phenotype in blood and synovium that is refractory to tumour necrosis factor (TNF) and IL-6R blockade. This study aimed to identify an alternative strategy to correct inflammation and metabolic dysfunction in these pathogenic MΦs.

METHODS: Peripheral blood-derived MΦs and synovial tissue from patients with RA, together with a localised arthritis model, were used to assess responses to succinate dehydrogenase (SDH) inhibition following TLR5 stimulation. We performed bulk RNA sequencing, Seahorse extracellular flux assays, flow cytometry, and multiscale immunofluorescence microscopy spanning whole RA synovium to individual mitochondria.

RESULTS: TLR5, SDH, and p65/NFKB1 colocalised in synovial CD14⁺ MΦs and were upregulated in circulation during disease flares. IL-1β⁺NFKB1⁺IFN-γ⁺STAT4^lo MΦs elicited by TLR5 stimulation exhibited biphasic metabolic reprogramming, with an early increase in mitochondrial adenosine triphosphate (ATP) production followed by tricarboxylic acid (TCA) cycle disruption, compensatory glycolysis, and SDH upregulation. In contrast to HK2 inhibition, which targets the first step of glycolysis, SDH inhibition within the TCA cycle intercepted TLR5-induced NF-κB/STAT4 signalling and oxidative stress, restoring TCA enzyme expression and mitochondrial function. In localised TLR5-driven synovitis, SDH inhibition attenuated joint inflammation by reducing the population of F4/80^⁺IL-1β⁺iNOS^⁺SDH^⁺ MΦs and restoring metabolic balance.

CONCLUSIONS: SDH functions as a metabolic-immune checkpoint in pathogenic IL-1β⁺NFKB1⁺IFN-γ⁺STAT4^lo MΦs in RA. Targeting SDH may concurrently resolve mitochondrial dysfunction and inflammation in patients experiencing disease flares, with synovial enrichment of TLR5, SDH, IL-1β, NFKB1, and IFN-γ serving as predictive biomarkers.

PMID:42697828 | DOI:10.1016/j.ard.2026.07.025