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However, the mechanisms underlying this differential pro\u2010inflammatory potential remain poorly defined. Using anti\u2010citrullinated protein IgA1 and IgA2 antibodies (ACPA) that are commonly found in rheumatoid arthritis (RA) patients and linked to chronic inflammation, we show here that, in macrophages, IgA2\u2010ICs boost TLR\u2010induced TNF and IL6 secretion, COX2 expression, and production of COX2\u2010dependent lipid mediators to a higher level than IgA1\u2010ICs. Metabolically, we found the amplification of TLR\u2010induced cytokine production and COX2 induction by IgA2\u2010ICs to be dependent on mitochondrial ATP synthesis, but not glycolysis. Finally, we found the potentiation of TLR\u2010induced cytokine production by IgA\u2010ICs to be COX2\u2010dependent. Together this work points towards a key role for mitochondrial ATP synthesis in driving COX2 expression and subsequent IgA2\u2010IC\u2010dependent potentiation of TLR\u2010induced cytokine production by macrophages. As such, our work provides new insights into the mechanisms underlying IgA2\u2010induced inflammation in the context of RA. Thus, this may hold novel clues to be explored as therapeutic possibilities to target antibody\u2010driven inflammation in chronic inflammatory diseases.<\/jats:p>","DOI":"10.1002\/eji.202451586","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T23:52:10Z","timestamp":1743724330000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["IgA2 ACPA Drives a Hyper\u2010Inflammatory Phenotype in Macrophages via ATP Synthase and COX2"],"prefix":"10.1002","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8656-3135","authenticated-orcid":false,"given":"Lu\u00eds","family":"Almeida","sequence":"first","affiliation":[{"name":"Centre for Infectious Diseases Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Bacon","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Ghorasaini","sequence":"additional","affiliation":[{"name":"Centre for Proteomics and Metabolomics Leiden University Medical Centre  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin J.","family":"van der Ham","sequence":"additional","affiliation":[{"name":"Centre for Infectious Diseases Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9618-6414","authenticated-orcid":false,"given":"Ren\u00e9 E. 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