Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: Roles of PPARγ and Th2 cytokines

Objective: Pharmacological activation of the nuclear receptor PPARγ is linked to numerous beneficial effects in the contexts of inflammation, lipid homeostasis, Type-2 Diabetes (T2D) and atherosclerosis. These beneficial effects include priming of circulating monocytes for differentiation towards an 'alternative' anti-inflammatory M2 macrophage phenotype. As we have recently shown that participation in low-intensity exercise increases PPARγ expression and activity in leukocytes from previously sedentary individuals, we aimed to elucidate whether low-intensity exercise elicited a pattern of gene expression similar to that reported for M2 monocyte-macrophage differentiation. Methods: 17 sedentary individuals undertook an 8-week low-intensity exercise programme (walking 10,000steps/day, three times/week). Changes in expression of PPARs and the PPARγ co-activators PGC-1_α and PGC-1_β; Th2 (IL-4; IL-10) and Th1 (IL-6) cytokines; and markers for the M2 (AMAC1, CD14, MR, IL-4) and the 'classical' pro-inflammatory M1 (MCP-1, TNFα, IL-6) phenotypes, were determined using RT-PCR (to assess leukocyte mRNA expression) and ELISA (to assess plasma cytokine levels). Results: Exercise was associated with upregulation of M2 markers, PGC-1_α and PGC-1_β, and with downregulation of M1 markers. Moreover, plasma levels of Th2 cytokines increased after exercise, while those of Th1 cytokines decreased. However, other PPARs (PPARα; PPARβ/δ) did not undergo marked exercise-induced activation or upregulation. Thus, participation in low-intensity exercise may prime monocytes for differentiation towards an M2 macrophage phenotype via PPARγ/PGC-1_α/β. Conclusion: Given the similarities between these effects and pharmacologically induced M2 polarisation, we propose that exercise-induced PPARγ/PGC-1_α/β-mediated M2 polarisation may constitute a novel anti-inflammatory benefit of low-intensity exercise.