Preventing the inflammatory polarization of monocyte/macrophage provides an effective therapy for rheumatoid arthritis-associated vascular injury.

Background

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Aims

Lipids depletion and cardiovascular diseases frequently coexist as complications in rheumatoid arthritis (RA). This work aimed to identify common pathogenic immune cells surrounding them and provide a basis for targeted therapy.

Methods

Candidate cells were screened via retrospective analyses of clinical data, and the result was validated by single-cell RNA sequencing of blood cells from patients with varying disease severity. Identified cells were isolated from healthy and RA individuals, and transplanted into mice to compare stimulating outcomes. Their functions were confirmed via co-culture with effector cells. Vascular injury (VI) was induced by balloons in adjuvant-induced arthritis (AIA) and healthy rats, with some rats receiving different treatments.

Results

RA patients were detected with reduced blood lipid levels, a phenomenon coincided with increased numbers of monocytes and neutrophils. Disease severity did not obviously affect monocytes, while inflammatory phenotype of neutrophils were reinforced only in severe RA. RA-derived neutrophils were rapidly cleared in recipients, and induced mild changes in the liver without causing immune perturbations. Besides metabolic alterations, RA monocytes induced inflammatory secretion of white adipose tissues (WAT) owing to the inflammatory function, long lifespan, and local enrichment. They accelerated lipid catabolism in HepG2 hepatocytes and endowed 3 T3-L1 adipocytes with an inflammatory secretion profile. In animal models, AIA exacerbated VI, with increased inflammatory macrophage aggregation in injured arteries. BAY 11-7085 (a NF-κB inhibitor) outperformed baricitinib and atorvastatin in reducing VI-caused mortality.

Conclusions

These findings indicate that monocytes/macrophages exacerbate VI in RA; preventing their inflammatory polarization will lower adverse cardiovascular events.