Highlights d Tuberculous pleural effusion (TB-PE) shifts glycolysis to OXPHOS in M1 macrophages d Metabolic shift is accompanied by low HIF-1a activity and high M. tuberculosis burden d HIF-1a stabilization reverts the metabolic shift and inhibitory effects of TB-PE d Host-derived lipids (eicosanoid-enriched fraction) in TB-PE drive the metabolic shift

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Objective. Itaconic acid, a Krebs cycle-derived immunometabolite, is synthesized by myeloid cells in response to danger signals to control inflammasome activation, type I interferon (IFN) responses, and oxidative stress. As these pathways are dysregulated in systemic lupus erythematosus (SLE), we investigated the role of an itaconic acid derivative in the treatment of established murine lupus.Methods. Female (NZW × NZB)F 1 lupus-prone mice were administered 4-octyl itaconate (4-OI) or vehicle starting after clinical onset of disease (30 weeks of age) for 4 weeks (n = 10 mice /group). At 34 weeks of age (peak disease activity), animals were euthanized, organs and serum were collected, and clinical, metabolic, and immunologic parameters were evaluated.Results. Proteinuria, kidney immune complex deposition, renal scores of severity and inflammation, and anti-RNP autoantibodies were significantly reduced in the 4-OI treatment group compared to the vehicle group. Splenomegaly decreased in the 4-OI group compared to vehicle, with decreases in activation markers in innate and adaptive immune cells, increases in CD8+ T cell numbers, and inhibition of JAK1 activation. Gene expression analysis in splenocytes showed significant decreases in type I IFN and proinflammatory cytokine genes and increased Treg cell-associated markers in the 4-OI group compared to the vehicle group. In human control and lupus myeloid cells, 4-OI in vitro treatment decreased proinflammatory responses and B cell responses.Conclusions. These results support targeting immunometabolism as a potentially viable approach in autoimmune disease treatment, with 4-OI displaying beneficial roles attenuating immune dysregulation and organ damage in lupus.

Obesity is a chronic inflammatory disease associated with adipose tissue macrophage (ATM) activation. ATMs from lean mice contribute to tissue homeostasis by their M2-oriented polarization, whereas obesity leads to an increase of M1 inflammatory ATMs that underlies obesity-related metabolic disorders. In humans, studies characterizing ATMs and their functional status are limited. Here we investigated ATM phenotype in visceral (VAT) and subcutaneous (SAT) adipose tissue from healthy lean and obese individuals using two molecules previously identified as markers of M1-like and M2-like/tissue-resident macrophages, the C-type lectin CLEC5A and the scavenger receptor CD163L1, respectively. CD163L1 was expressed by the majority of ATMs, and CD163L1 + ATM density was greater with respect to cells expressing the pan-macrophage markers CD68 or CD11b. ATM counts in SAT, but not in VAT, increased in obese compared to lean individuals, measured with the three markers. Accordingly, CD163L1, CD68 and ITGAM gene expression was significantly enhanced in obese with respect to control individuals only in SAT. CLEC5A + ATMs had a proinflammatory profile and were abundant in the lean VAT, but their density diminished in obesity. The only ATM subset that increased its counts in the obese VAT had a mixed M1-like (CD11c + CD163 À CD209 À) and M2-like (CLEC5A À CD206 +) phenotype. ATM expansion was dominated by a subset of M2-like macrophages (CD11c À CLEC5A À CD163 + CD206 + CD209 +) in the obese SAT, with a minor contribution of a CD11c + CLEC5A À ATM subpopulation. Thus, both SAT and VAT seems to limit inflammation during obesity by differentially altering their ATM subset composition.