PKM2 Promotes Pro-Inflammatory Macrophage Activation in Ankylosing Spondylitis.

Macrophages play a critical role in ankylosing spondylitis (AS) by promoting autoimmune tissue inflammation through various effector functions. The inflammatory potential of macrophages is highly influenced by their metabolic environment. Here, we demonstrate that glycolysis is linked to the pro-inflammatory activation of human blood monocyte-derived macrophages (MDMs) in AS. Specifically, AS macrophages produced excessive inflammation, including TNFα, IL1β, and IL23, and displayed an overactive status by exhibiting stronger co-stimulatory signals, such as CD80, CD86, and HLA-DR. Moreover, we found that patient-derived monocyte-derived M1 type macrophages (M1 macrophages) exhibited intensified glycolysis, as evidenced by higher extracellular acidification rate (ECAR). Upregulation of PKM2 and GLUT1 was observed in AS-derived monocytes and MDMs, especially in M1 macrophages, indicating glucose metabolic alteration in AS macrophages. To investigate the impact of glycolysis on macrophage inflammatory ability, we treated AS M1 macrophages with two inhibitors: 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, and Shikonin, a PKM2 inhibitor. Both inhibitors reduced pro-inflammatory function and reversed the overactive status of AS macrophages, suggesting their potential utility in treating the disease. These data place PKM2 at the cross-talk between glucose metabolic changes and the activation of inflammatory macrophages in AS patients.