Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation

Abstract

Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…Vats and colleagues highlighted the importance of mitochondrial oxidative phosphorylation in the induction of M2-type macrophages through IL-4 signaling. They observed that mitochondrial inhibition in macrophages blocked the antiinflammatory effects of IL-4 (30). In the present study, addition of the mitochondrial inhibitor oligomycin prevented the suppression of TNF-a and the enhancement of phagocytosis in macrophages by MSC CM, demonstrating that the MSCs' effect is critically dependent on oxidative phosphorylation ( Figures 6A and 6B).…”

“…The influence of mitochondrial transfer on macrophage phenotype, however, has not been studied extensively. Vats and colleagues showed the importance of mitochondrial oxidative phosphorylation in the induction of IL-4-induced antiinflammatory M2 macrophage polarization (30). Indeed, glucose metabolism is intrinsically linked to a macrophage activation state with M1 proinflammatory macrophages using glycolysis (31).…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…On the other hand, M2 macrophages are scattered in interstitial spaces between adipocytes [20]. It is known that M1 macrophages are induced by proinflammatory mediators such as lipopolysaccharide (LPS) and Th1 cytokine interferon-γ (IFN-γ), whereas M2 macrophages are polarized by the stimulation with Th2 cytokines such as interleukin-4 (IL-4) and IL-13 [19,22]. Recent studies have also shown that epigenetic changes and noncoding RNAs are involved in macrophage polarization [23,24].…”

Molecular mechanism underlying nutritional control of inflammatory responses

“…TLR4-deficiency protects against obesity-induced adipose tissue inflammation without affecting body weight gain. On the other hand, M2 macrophages are polarized by stimulation with Th2 cytokines such as interleukin-4 (IL-4) and peroxisome proliferator-activated receptors (PPARδ and PPARγ) [31][32][33]38) . Deficiency of PPARδ or PPARγ, specifically in macrophages, exacerbates obesity-induced adipose tissue inflammation and glucose intolerance.…”