Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization

Abstract

The anti-inflammatory effects of globular adiponectin (gAcrp) are mediated by IL-10/heme oxygenase 1 (HO-1)-dependent pathways. Although full-length (flAcrp) adiponectin also suppresses LPS-induced pro-inflammatory signaling, its signaling mechanisms are not yet understood. The aim of this study was to examine the differential mechanisms by which gAcrp and flAcrp suppress pro-inflammatory signaling in macrophages. Chronic ethanol feeding increased LPS-stimulated TNF-␣ expression by Kupffer cells, associated with a shift to an M1 macrophage polarization. Both gAcrp and flAcrp suppressed TNF-␣ expression in Kupffer cells; however, only the effect of gAcrp was dependent on IL-10. Similarly, inhibition of HO-1 activity or siRNA knockdown of HO-1 in RAW264.7 macrophages only partially attenuated the suppressive effects of flAcrp on MyD88-dependent and -independent cytokine signatures. Instead, flAcrp, acting via the adiponectin R2 receptor, potently shifted the polarization of Kupffer cells and RAW264.7 macrophages to an M2 phenotype. gAcrp, acting via the adiponectin R1 receptor, was much less effective at eliciting an M2 pattern of gene expression. M2 polarization was also partially dependent on AMPactivated kinase. flAcrp polarized RAW264.7 macrophages to an M2 phenotype in an IL-4/STAT6-dependent mechanism. flAcrp also increased the expression of genes involved in oxidative phosphorylation in RAW264.7 macrophages, similar to the effect of flAcrp on hepatocytes. In summary, these data demonstrate that gAcrp and flAcrp utilize differential signaling strategies to decrease the sensitivity of macrophages to activation by TLR4 ligands, with flAcrp utilizing an IL-4/ STAT6-dependent mechanism to shift macrophage polarization to the M2/anti-inflammatory phenotype.Resident tissue macrophages exhibit a tremendous plasticity in their response to external stimuli. In particular, the local metabolic and immune microenvironment contributes to this plasticity (1). In response to different stimuli, macrophages express distinct patterns of surface receptors and metabolic enzymes that ultimately generate the diversity of macrophage functions. Although the precise characterization of macrophage diversity is continuing to evolve, two distinct polarization states of macrophages, M1 and M2, have been characterized (1, 2). LPS and IFN␥ can promote macrophage differentiation to a "classical" or M1 phenotype (1). The M1 activation pattern is associated with tissue destruction and inflammation and is responsible for up-regulating pro-inflammatory cytokines and increasing production of reactive nitrogen species and reactive oxygen species (1). In contrast, the "alternative" or M2 activation phenotype of macrophages is induced in response to IL-4 and IL-13. M2-polarized macrophages dampen the inflammatory process by producing anti-inflammatory factors, such as IL-10 and TGF␤. M2 macrophages also up-regulate mannose receptors, such as the macrophage mannose receptor (MMR) 2 and mannose receptor, C type 2 (Mrc2c), IL-1 receptor antagonist (I...

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

“…Mouse RAW264.7 macrophages have been shown to exhibit a differentiation ability toward two phenotypes, M1 or M2: (i) their treatment with antigens/cytokines, such as lipopolysaccharide (LPS), can induce the M1 phenotype associated with increased secretion of TNF‐α (anticancer activity)25 and (ii) treatment with IL‐4 can lead to the M2 phenotype associated with increased secretion of TGF‐β (pro‐cancer activity) 26. In our study, treatment with Aneustat did not affect the proliferation of the RAW264.7 cells (Fig.…”

Potential Molecular Mechanism of Probiotics in Alcoholic Liver Disease

“…Both gAcrp and flAcrp suppressed TNF-α expression in Kupffer cells; however, only the effect of gAcrp was dependent on IL-10. Their data demonstrated that gAcrp and flAcrp utilize differential signaling strategies to reduce the sensitivity of macrophages to activation by TLR4 ligands, with flAcrp utilizing an IL-4/STAT6-dependent mechanism to shift macrophage polarization to the M2/anti-inflammatory phenotype [40]. Some recent literature suggested an increase in LPS (TLR4) resulting in elevation of miR-155 and TNF-α stability in isolated Kupffer cells in ALD mouse model [41].…”

Insulin resistance pathogenesis in metabolic obesity

“…Учитывая тот факт, что макрофаги способствуют гипертрофии адипоцитов, следует признать, что при ожирении имеет место порочный круг с положительной обратной связью: гипертрофированные адипоциты продуцируют хемокины и их рецепторы, которые инициируют рекрутирование моноцитов/макрофагов в ЖТ. Последние способствуют дальнейшей гипертрофии адипоцитов, часть из которых гибнет, образуя при этом DAMPS, и, кроме того, вырабатывают белки адгезии и СЖК, что, в конечном итоге, способствует дальнейшей пролонгации воспалительной реакции [54].Адипонектин непосредственно способствует дифференцировке макрофагов в противо-воспалительный фенотип -М2, воздействуя на рецепторы -AdipoR1 и AdipoR2: AdipoR1 ® IL-10 ® HO-1-зависимый путь, уменьшающий экспрессию TLR4 и AdipoR2 ® IL-4 ® STAT6-зависимый сигнальный путь, который снижает выработку провоспалительных цитокинов [61]. Между экспрессией мРНК генов адипонектина и IkB-a, ингибирующего транскрипционную активность NF-kВ, выявлена сильная взаимосвязь.…”

“…Адипонектин непосредственно способствует дифференцировке макрофагов в противо-воспалительный фенотип -М2, воздействуя на рецепторы -AdipoR1 и AdipoR2: AdipoR1 ® IL-10 ® HO-1-зависимый путь, уменьшающий экспрессию TLR4 и AdipoR2 ® IL-4 ® STAT6-зависимый сигнальный путь, который снижает выработку провоспалительных цитокинов [61]. Между экспрессией мРНК генов адипонектина и IkB-a, ингибирующего транскрипционную активность NF-kВ, выявлена сильная взаимосвязь.…”