Metabolic reprogramming of macrophages instigates CCL21-induced arthritis

This study was designed to delineate the functional significance of CCL21 in metabolic reprogramming in experimental arthritis and differentiated rheumatoid arthritis (RA) macrophages (M phi s). To characterize the influence of CCL21 on immunometabolism, its mechanism of action was elucidated by dysregulating glucose uptake in preclinical arthritis and RA M phi s. In CCL21 arthritic joints, the glycolytic intermediates hypoxia-inducible factor 1 alpha (HIF1 alpha), cMYC and GLUT1 were overexpressed compared with oxidative regulators estrogen-related receptor gamma and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1)-alpha. Interestingly, 2-deoxy-D-glucose (2-DG) therapy mitigated CCL21-induced arthritis by restraining the number of joint F4/80(+)iNOS(+)M phi s without impacting F4/80(+)Arginase(+)M phi s. Similar to the preclinical findings, blockade of glycolysis negated CCL21-polarized CD14(+)CD86(+)GLUT(+)M phi frequency; however, CD14(+)CD206(+)GLUT(+)M phi s were not implicated in this process. In CCL21-induced arthritis and differentiated RA M phi s, the inflammatory imprint was uniquely intercepted by 2-DG via interleukin-6 (IL-6) downregulation. Despite the more expansive inflammatory response of CCL21 in the arthritic joints relative to the differentiated RA M phi s, 2-DG was ineffective in joint tumor necrosis factor-alpha, IL-1 beta, CCL2 and CCL5 enrichment. By contrast, disruption of glycolysis markedly impaired CCL21-induced HIF1 alpha and cMYC signaling in arthritic mice. Notably, in RA M phi s, glycolysis interception was directed toward dysregulating CCL21-enhanced HIF1 alpha transcription. Nonetheless, in concurrence with the diminished IL-6 levels, CCL21 differentiation of CD14(+)CD86(+)GLUT1(+)M phi s was reversed by glycolysis and HIIF1 alpha inhibition. Moreover, in the CCL21 experimental arthritis or differentiated RA M phi s, the malfunctioning metabolic machinery was accompanied by impaired oxidative phosphorylation because of reduced PGC1 alpha or peroxisome proliferator-activated receptor-gamma expression. CCL21 reconfigures naive myeloid cells into glycolytic RA CD14(+)CD86(+)GLUT(+)IL-6(high)HIF1 alpha(high) M phi s. Therefore, inhibiting the CCL21/CCR7 pathway may provide a promising therapeutic strategy.