Annals of the rheumatic diseases
September 4, 2026 · via Europe PMC
SDH inhibition quenches rheumatoid arthritis flare-associated IL-1β<sup>+</sup>IFN-γ<sup>+</sup> macrophages via NF-κB/STAT4.
Zack SR, Satoeya N, Sosa Hernández VA, +14 more, Shahrara S.
AI summary — for doctors, generated from the abstract only
In laboratory and mouse models, inhibiting an enzyme called succinate dehydrogenase (SDH) reduced inflammation and restored metabolic function in a specific pathogenic macrophage type linked to rheumatoid arthritis flares that is resistant to standard TNF and IL-6 blocking drugs, suggesting a potential new drug target.
What was studied
A mechanistic study using peripheral blood-derived macrophages and synovial tissue from RA patients, plus a localized mouse arthritis model, to test the effects of succinate dehydrogenase (SDH) inhibition on a TLR5-driven, treatment-resistant IL-1β+IFN-γ+ macrophage phenotype linked to RA disease flares, using RNA sequencing, metabolic flux assays, flow cytometry, and multiscale imaging.
Key findings
- TLR5, SDH, and p65/NFKB1 co-localized in synovial CD14+ macrophages and were upregulated in circulation during disease flares.
- The pathogenic macrophage phenotype showed biphasic metabolic reprogramming: an early increase in mitochondrial ATP production followed by TCA cycle disruption and compensatory glycolysis with SDH upregulation.
- SDH inhibition (unlike HK2/glycolysis inhibition) intercepted NF-κB/STAT4 signaling and oxidative stress, restoring TCA enzyme expression and mitochondrial function.
- In a mouse model of TLR5-driven synovitis, SDH inhibition reduced joint inflammation by decreasing the population of pathogenic F4/80+IL-1β+iNOS+SDH+ macrophages and restored metabolic balance.
Clinical relevance
The findings suggest SDH could represent a novel therapeutic target for RA patients with treatment-resistant macrophage-driven flares that do not respond to TNF or IL-6 blockade, which could eventually open new treatment avenues for refractory RA, but this is preclinical cell and mouse model research, not evidence of efficacy or safety in human patients.
Who should care
Limitations
This is preclinical research using human cells ex vivo and a mouse model; findings have not been tested in human clinical trials, and translation to an actual RA therapy is not established.
Targeting a metabolic enzyme (SDH) reduced inflammation in a treatment-resistant macrophage type linked to RA flares in preclinical models, suggesting a potential new therapeutic strategy for refractory disease.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
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+STAT4lo 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+STAT4lo 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+STAT4lo 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.
DOI
10.1016/j.ard.2026.07.025
PMID
42697828
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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