Metabolic reprogramming of macrophages instigates CCL21-induced arthritis
| Autor: | Katrien Van Raemdonck, Shiva Shahrara, Huan J Chang, Sadiq Umar, Anja Meyer, Ryan K Zomorrodi, Mina Al-Awqati, Michael V. Volin, Karol Palasiewicz |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
endocrine system
Chemistry Interleukin-6 Tumor Necrosis Factor-alpha Glucose uptake Macrophages Immunology Arthritis Cell Biology CCL2 medicine.disease CCL5 Article Arginase Arthritis Rheumatoid Mice Downregulation and upregulation Cancer research medicine Immunology and Allergy Animals Glycolysis Tumor necrosis factor alpha |
| Zdroj: | Immunol Cell Biol |
| Popis: | The current study was designed to delineate the functional significance of CCL21 on metabolic reprogramming in experimental arthritis and rheumatoid arthritis (RA) differentiated macrophages (MΦs). To characterize the influence of CCL21 on immunometabolism, its mechanism of action was elucidated by dysregulating glucose uptake in preclinical arthritis and RA MΦs. In CCL21 arthritic joints, the glycolytic intermediates, HIF1α, cMYC, and GLUT1 were overexpressed compared to oxidative regulators, ESSRγ and PGC1α. Interestingly, 2-DG therapy mitigated CCL21-induced arthritis by restraining the number of joint F480(+)iNOS(+)MΦs without impacting F480(+)Arginase(+)MΦs. Similar to the preclinical findings, blockade of glycolysis negated CCL21-polarized CD14(+)CD86(+)GLUT(+)MΦ frequency; however, CD14(+)CD206(+)GLUT(+)MΦs were not implicated in this process. In CCL21-induced arthritis and differentiated RA MΦs, the inflammatory imprint was uniquely intercepted by 2-DG via IL-6 downregulation. Despite, the more expansive inflammatory response of CCL21 in the arthritic joints relative to the differentiated RA MΦs, 2-DG was ineffective on joint TNFα, IL-1β, CCL2, and CCL5 enrichment. In contrast, disruption of glycolysis markedly impaired CCL21-induced HIF1α and cMYC signaling in arthritic mice. Notably, in RA MΦs, glycolysis interception was directed on dysregulating CCL21-enhanced HIF1α transcription. Nonetheless, in concurrence with the diminished IL-6 levels, CCL21-differentiation of CD14(+)CD86(+)GLUT1(+)MΦs was reversed by glycolysis and HIIF1α inhibition. Moreover, in the CCL21 experimental arthritis or differentiated RA MΦs, the malfunctioning metabolic machinery was accompanied by impaired oxidative phosphorylation due to reduced PGC1α or PPARγ expression. CCL21 reconfigures naïve myeloid cells into glycolytic RA CD14(+)CD86(+)GLUT(+)IL-6(high)HIF1α(high) MΦs, thus inhibiting the CCL21/CCR7 pathway may provide a promising therapeutic strategy. |
| Databáze: | OpenAIRE |
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