PKA regulatory IIα subunit is essential for PGD2-mediated resolution of inflammation.
The kinetic participation of macrophages is critical for inflammatory resolution and recovery from myocardial infarction (MI), particularly with respect to the transition from the M1 to the M2 phenotype; however, the underlying mechanisms are poorly understood. In this study, we found that the deletion of prostaglandin (PG) D2 receptor subtype 1 (DP1) in macrophages retarded M2 polarization, antiinflammatory cytokine production, and resolution in different inflammatory models, including the MI model. DP1 deletion up-regulated proinflammatory genes expression via JAK2/STAT1 signaling in macrophages, whereas its activation facilitated binding of the separated PKA regulatory IIα subunit (PRKAR2A) to the transmembrane domain of IFN-γ receptor, suppressed JAK2-STAT1 axis-mediated M1 polarization, and promoted resolution. PRKAR2A deficiency attenuated DP1 activation-mediated M2 polarization and resolution of inflammation. Collectively, PGD2-DP1 axis-induced M2 polarization facilitates resolution of inflammation through the PRKAR2A-mediated suppression of JAK2/STAT1 signaling. These observations indicate that macrophage DP1 activation represents a promising strategy in the management of inflammation-associated diseases, including post-MI healing.
Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Deping
0000-0003-3350-7599
D
Kong
Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Yujun
Y
Shen
Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Guizhu
0000-0003-3242-8717
G
Liu
Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Shengkai
S
Zuo
The Key Laboratory of Cardiovascular Disease and Molecular Intervention, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Yong
Y
Ji
Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Ankang
0000-0001-6662-8624
A
Lu
Human Gene Sciences Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
Masataka
M
Nakamura
International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba City, Ibaraki 305-8575, Japan.
Michael
0000-0003-3863-4474
M
Lazarus
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Constantine A
CA
Stratakis
Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37212 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
Richard M
0000-0001-5828-4403
RM
Breyer
Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China yuying@sibs.ac.cn yuying@tmu.edu.cn.
Ying
Y
Yu
D000818:Animals; D002432:Cecum / Q000473:pathology; D016764:Cell Polarity; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006827:Hydantoins; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D053614:Janus Kinase 2 / Q000378:metabolism; D008026:Ligation; D008264:Macrophages / Q000166:cytology; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology; D010538:Peritonitis / Q000473:pathology; D015230:Prostaglandin D2 / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D011677:Punctures; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing; D015054:Zymosan
D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D006827:Hydantoins; C490116:Ifngr2 protein, mouse; C517821:Prkar2a protein, mouse; D021122:Protein Subunits; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D011982:Receptors, Prostaglandin; D050794:STAT1 Transcription Factor; C527097:prostanoid D receptor 1, mouse; C087760:3-((2-cyclohexyl-2-hydroxyethylidene)amino)-2,5-dioxo-4-imidazolidineheptanoic acid; D015054:Zymosan; D053614:Janus Kinase 2; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor