Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue

Persistent activation of the innate immune system greatly influences the risk for developing metabolic complications associated with obesity. In this study, we explored the therapeutic potential of the specialized proresolving mediator (SPM) resolvin D1 (RvD1) to actively promote the resolution of inflammation in human visceral adipose tissue from obese (Ob) patients. Using liquid chromatography–tandem mass spectrometry–based metabololipidomic analysis, we identified unbalanced production of SPMs (i.e., D- and E-series resolvins, protectin D1, maresin 1, and lipoxins) with respect to inflammatory lipid mediators (i.e., leukotriene B4 and PGs) in omental adipose tissue from Ob patients. In parallel, high-throughput transcriptomic analysis revealed a unique signature in this tissue that was characterized by overactivation of the IL-10 signaling pathway. Incubation of inflamed Ob visceral adipose tissues and human macrophages with RvD1 limited excessive activation of the IL-10 pathway by reducing phosphorylation of STAT proteins. Of interest, RvD1 blocked STAT-1 and its target inflammatory genes (i.e., CXCL9), as well as persistent STAT3 activation, without affecting the IL-10 anti-inflammatory response characterized by inhibition of IL-6, IL-1β, IL-8, and TNF-α. Furthermore, RvD1 promoted resolution by enhancing expression of the IL-10 target gene heme oxygenase-1 by mechanisms dependent on p38 MAPK activity. Together, our data show that RvD1 can tailor the quantitative and qualitative responses of human inflamed adipose tissue to IL-10 and provide a mechanistic basis for the immunoresolving actions of RvD1 in this tissue. These findings may have potential therapeutic implications in obesity-related insulin resistance and other metabolic complications.

[1]  C. Serhan,et al.  Resolvins attenuate inflammation and promote resolution in cigarette smoke-exposed human macrophages. , 2015, American journal of physiology. Lung cellular and molecular physiology.

[2]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[3]  Yuka Kanno,et al.  Mechanisms of Jak/STAT Signaling in Immunity and Disease , 2015, The Journal of Immunology.

[4]  C. Serhan,et al.  Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. , 2014, American journal of physiology. Cell physiology.

[5]  Charles N. Serhan,et al.  Pro-resolving lipid mediators are leads for resolution physiology , 2014, Nature.

[6]  D. Miranda-Saavedra,et al.  Protein Tyrosine Phosphatase 1B Is a Regulator of the Interleukin-10–Induced Transcriptional Program in Macrophages , 2014, Science Signaling.

[7]  V. Arroyo,et al.  Resolvin D1 primes the resolution process initiated by calorie restriction in obesity‐induced steatohepatitis , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  C. Serhan,et al.  Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. , 2014, Cell metabolism.

[9]  M. Perretti,et al.  Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses , 2013, Proceedings of the National Academy of Sciences.

[10]  S. Mackay,et al.  Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells , 2013, The Biochemical journal.

[11]  C. Serhan,et al.  Diversity of lipid mediators in human adipose tissue depots. , 2013, American journal of physiology. Cell physiology.

[12]  F. Gao,et al.  Resolvin D1 and Resolvin D2 Govern Local Inflammatory Tone in Obese Fat , 2012, The Journal of Immunology.

[13]  V. Arroyo,et al.  Resolvin D1 and Its Precursor Docosahexaenoic Acid Promote Resolution of Adipose Tissue Inflammation by Eliciting Macrophage Polarization toward an M2-Like Phenotype , 2011, The Journal of Immunology.

[14]  A. Yoshimura,et al.  IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. , 2011, International immunology.

[15]  A. Chawla,et al.  Macrophage-mediated inflammation in metabolic disease , 2011, Nature Reviews Immunology.

[16]  Yunan Tang,et al.  Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese‐diabetic mice , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  C. Serhan,et al.  Saturated‐efferocytosis generates pro‐resolving CD11blow macrophages: Modulation by resolvins and glucocorticoids , 2011, European journal of immunology.

[18]  K. Walsh,et al.  Adipokines in inflammation and metabolic disease , 2011, Nature Reviews Immunology.

[19]  M. Gaestel,et al.  Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation , 2010, Journal of Cell Science.

[20]  V. Arroyo,et al.  Obesity‐induced insulin resistance and hepatic steatosis are alleviated by ω‐3 fatty acids: a role for resolvins and protectins , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  A. Ferrante,et al.  Obesity‐induced inflammation: a metabolic dialogue in the language of inflammation , 2007, Journal of internal medicine.

[22]  D. Levy,et al.  JAK-STAT Signaling: From Interferons to Cytokines* , 2007, Journal of Biological Chemistry.

[23]  Charles N. Serhan,et al.  Resolvin E1 and protectin D1 activate inflammation-resolution programmes , 2007, Nature.

[24]  Masato Kubo,et al.  SOCS proteins, cytokine signalling and immune regulation , 2007, Nature Reviews Immunology.

[25]  G. Hotamisligil,et al.  Inflammation and metabolic disorders , 2006, Nature.

[26]  W. Alexander,et al.  General Nature of the STAT3-Activated Anti-Inflammatory Response1 , 2006, The Journal of Immunology.

[27]  N. Abraham,et al.  CD163-Mediated hemoglobin-heme uptake activates macrophage HO-1, providing an antiinflammatory function. , 2006, Circulation research.

[28]  J. Ashwell The many paths to p38 mitogen-activated protein kinase activation in the immune system , 2006, Nature Reviews Immunology.

[29]  John Savill,et al.  Resolution of inflammation: the beginning programs the end , 2005, Nature Immunology.

[30]  Adriano G. Rossi,et al.  Inflammatory Resolution: new opportunities for drug discovery , 2004, Nature Reviews Drug Discovery.

[31]  D. Giannella‐Neto,et al.  Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. , 2002, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[32]  Tzong-Shyuan Lee,et al.  Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice , 2002, Nature Medicine.

[33]  Y. Liu,et al.  IL‐10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3‐dependent and ‐independent pathways , 1998, The EMBO journal.

[34]  C. Gabay,et al.  Interleukin-1 receptor antagonist: role in biology. , 1998, Annual review of immunology.