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CTRP6 as a negative regulator of anti-inflammatory M2 macrophage polarization

CTRP6 as a negative regulator of anti-inflammatory M2 macrophage polarization

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DOI	10.1097/IN9.0000000000000070
刊名	Immunometabolism IJ
年，卷(期)	2025, 7(4)
作者	Senthil Kumar, Jeevotham; Kempton, Emma; Mehboob, Muhammad Zubair; Lin, Dingbo; Lei, Xia,
作者单位	Oklahoma State Univ, Dept Biochem Mol Biol, Stillwater, OK 74078 USA; [Lin, Dingbo
摘要	Background:Chronic low-grade inflammation in adipose tissue, primarily driven by macrophages, plays a central role in obesity pathophysiology. C1q/TNF-related protein 6 (CTRP6), a member of the CTRP family, has emerged as a key regulator of this inflammatory process. Here, we demonstrate that CTRP6 expression is upregulated in adipose tissue macrophages during obesity, where it acts as a potent modulator of macrophage polarization by suppressing M2 polarization.Methods:In RAW264.7 macrophages, we distinguished M1 and M2 polarization, induced by lipopolysaccharide (LPS) + interferon-gamma (IFN gamma) and interleukin (IL)-4, respectively, by selecting two marker genes for each polarization type from a set of five widely used markers, based on a time-course analysis. We then assessed the effects of recombinant CTRP6 protein treatment on M1 and M2 polarization. Finally, we validated our findings in primary bone marrow-derived macrophages (BMDMs).Results:In na & iuml;ve RAW264.7 macrophages, recombinant CTRP6 protein upregulated M1 marker genes (Tnf, Nos2) while downregulating M2 markers (Mrc1, Pparg). During M1 polarization induced by LPS+IFN gamma, CTRP6 treatment had no significant effect. However, during IL-4-induced M2 polarization, CTRP6 not only enhanced M1 markers but also strongly suppressed M2 markers by inhibiting anti-inflammatory signal transducer and activator of transcription 6 (STAT6) signaling and relieving the inhibition of pro-inflammatory ERK1/2 signaling. Additionally, CTRP6 impaired mitochondrial activity, favoring glycolysis in macrophages. Importantly, these effects were serum-independent and confirmed in BMDMs.Conclusions:Since endogenous CTRP6 expression in BMDMs is upregulated by M1 polarization inducers, it may further hinder inflammation resolution, even in the presence of IL-4 during tissue repair, establishing it as a key driver of adipose tissue inflammation in obesity.
Abstract	Background:Chronic low-grade inflammation in adipose tissue, primarily driven by macrophages, plays a central role in obesity pathophysiology. C1q/TNF-related protein 6 (CTRP6), a member of the CTRP family, has emerged as a key regulator of this inflammatory process. Here, we demonstrate that CTRP6 expression is upregulated in adipose tissue macrophages during obesity, where it acts as a potent modulator of macrophage polarization by suppressing M2 polarization.Methods:In RAW264.7 macrophages, we distinguished M1 and M2 polarization, induced by lipopolysaccharide (LPS) + interferon-gamma (IFN gamma) and interleukin (IL)-4, respectively, by selecting two marker genes for each polarization type from a set of five widely used markers, based on a time-course analysis. We then assessed the effects of recombinant CTRP6 protein treatment on M1 and M2 polarization. Finally, we validated our findings in primary bone marrow-derived macrophages (BMDMs).Results:In na & iuml;ve RAW264.7 macrophages, recombinant CTRP6 protein upregulated M1 marker genes (Tnf, Nos2) while downregulating M2 markers (Mrc1, Pparg). During M1 polarization induced by LPS+IFN gamma, CTRP6 treatment had no significant effect. However, during IL-4-induced M2 polarization, CTRP6 not only enhanced M1 markers but also strongly suppressed M2 markers by inhibiting anti-inflammatory signal transducer and activator of transcription 6 (STAT6) signaling and relieving the inhibition of pro-inflammatory ERK1/2 signaling. Additionally, CTRP6 impaired mitochondrial activity, favoring glycolysis in macrophages. Importantly, these effects were serum-independent and confirmed in BMDMs.Conclusions:Since endogenous CTRP6 expression in BMDMs is upregulated by M1 polarization inducers, it may further hinder inflammation resolution, even in the presence of IL-4 during tissue repair, establishing it as a key driver of adipose tissue inflammation in obesity.
关键词	CTRP6; adipose tissue; inflammation; negative regulator; M2 macrophage polarization
KeyWord	CTRP6; adipose tissue; inflammation; negative regulator; M2 macrophage polarization
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Senthil Kumar, Jeevotham; Kempton, Emma; Mehboob, Muhammad Zubair; Lin, Dingbo; Lei, Xia. CTRP6 as a negative regulator of anti-inflammatory M2 macrophage polarization [J]. Immunometabolism. 2025; 7; (4). - .

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