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Lactate-p300 activates macrophage-fibroblast-like synoviocytes communication via H3K18la to promote rheumatoid arthritis

ABSTRACT: This study investigated the role of lactate‑induced histone H3K18 lactylation (H3K18la) in the pathology of rheumatoid arthritis (RA).Immunohistochemistry, western blot, gene knockdown/overexpression, proteomics, transwell co‑culture, and flow cytometry were employed to explore the function and mechanism of H3K18la in RA.Results demonstrated that elevated lactate levels in M1 macrophages promote H3K18la through p300, leading to the upregulation of METTL16 in these macrophages.When co‑cultured with M1 macrophages, fibroblast‑like synoviocytes (FLS) showed enhanced Wnt/β‑catenin signaling (increased expression of Wnt1) and elevated levels of pro‑invasive markers including MMP3 and fibronectin. These effects were abolished by p300 knockdown in macrophages, but restored by enforced overexpression of METTL16.In conclusion, lactate‑p300‑mediated H3K18la in M1 macrophages drives RA progression via METTL16/Wnt1‑dependent crosstalk with FLS, linking lactate metabolism and histone lactylation in M1 macrophages to the pathogenesis of RA.

ORGANISM(S): Homo Sapiens

SUBMITTER: Chenggui Miao

PROVIDER: PXD075185 | iProX | Wed Mar 04 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS

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Lactate-p300 activates macrophage-fibroblast-like synoviocytes communication via H3K18la to promote rheumatoid arthritis

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