Novel Resolvin D2 Receptor Axis in Infectious Inflammation

被引:140
作者
Chiang, Nan
de la Rosa, Xavier
Libreros, Stephania
Serhan, Charles N. [1 ,2 ]
机构
[1] Brigham & Womens Hosp, Bldg Transformat Med,Suite 3-016,60 Fenwood Rd, Boston, MA 02115 USA
[2] Harvard Med Sch, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
LIPID MEDIATORS; TRANSGENIC MICE; RESOLUTION; SEPSIS; D1; IDENTIFICATION; ACTIVATION; CIRCUITS; SIGNALS; MODEL;
D O I
10.4049/jimmunol.1601650
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Resolution of acute inflammation is an active process governed by specialized proresolving mediators, including resolvin (Rv)D2, that activates a cell surface G protein-coupled receptor, GPR18/DRV2. In this study, we investigated RvD2-DRV2-dependent resolution mechanisms using DRV2-deficient mice (DRV2-knockout [KO]). In polymicrobial sepsis initiated by cecal ligation and puncture, RvD2 (similar to 2.7 nmol/mouse) significantly increased survival (>50%) of wild-type mice and reduced hypothermia and bacterial titers compared with vehicle-treated cecal ligation and puncture mice that succumbed at 48 h. Protection by RvD2 was abolished in DRV2-KO mice. Mass spectrometry-based lipid mediator metabololipidomics demonstrated that DRV2-KO infectious exudates gave higher proinflammatory leukotriene B-4 and procoagulating thromboxane B-2, as well as lower specialized proresolving mediators, including RvD1 and RvD3, compared with wild-type. RvD2-DRV2-initiated intracellular signals were investigated using mass cytometry (cytometry by time-of-flight), which demonstrated that RvD2 enhanced phosphorylation of CREB, ERK1/2, and STAT3 in WT but not DRV2-KO macrophages. Monitored by real-time imaging, RvD2-DRV2 interaction significantly enhanced phagocytosis of live Escherichia coli, an action dependent on protein kinase A and STAT3 in macrophages. Taken together, we identified an RvD2/DRV2 axis that activates intracellular signaling pathways that increase phagocytosis-mediated bacterial clearance, survival, and organ protection. Moreover, these results provide evidence for RvD2-DRV2 and their downstream pathways in pathophysiology of infectious inflammation.
引用
收藏
页码:842 / 851
页数:10
相关论文
共 53 条
[1]   Human milk proresolving mediators stimulate resolution of acute inflammation [J].
Arnardottir, H. ;
Orr, S. K. ;
Dalli, J. ;
Serhan, C. N. .
MUCOSAL IMMUNOLOGY, 2016, 9 (03) :757-766
[2]   Molecular circuits of resolution: Formation and actions of resolvins and protectins [J].
Bannenberg, GL ;
Chiang, N ;
Ariel, A ;
Arita, M ;
Tjonahen, E ;
Gotlinger, KH ;
Hong, S ;
Serhan, CN .
JOURNAL OF IMMUNOLOGY, 2005, 174 (07) :4345-4355
[3]   Omega-3 Fatty Acid-Derived Mediators 17(R)-Hydroxy Docosahexaenoic Acid, Aspirin-Triggered Resolvin D1 and Resolvin D2 Prevent Experimental Colitis in Mice [J].
Bento, Allisson Freire ;
Claudino, Rafaela Franco ;
Dutra, Rafael Cypriano ;
Marcon, Rodrigo ;
Calixto, Joao B. .
JOURNAL OF IMMUNOLOGY, 2011, 187 (04) :1957-1969
[4]   Resolvin D2 prevents secondary thrombosis and necrosis in a mouse burn wound model [J].
Bohr, Stefan ;
Patel, Suraj J. ;
Sarin, Dhruv ;
Irimia, Daniel ;
Yarmush, Martin L. ;
Berthiaume, Francois .
WOUND REPAIR AND REGENERATION, 2013, 21 (01) :35-43
[5]   DEFINITIONS FOR SEPSIS AND ORGAN FAILURE AND GUIDELINES FOR THE USE OF INNOVATIVE THERAPIES IN SEPSIS [J].
BONE, RC ;
BALK, RA ;
CERRA, FB ;
DELLINGER, RP ;
FEIN, AM ;
KNAUS, WA ;
SCHEIN, RMH ;
SIBBALD, WJ .
CHEST, 1992, 101 (06) :1644-1655
[6]   Animal models of sepsis: Setting the stage [J].
Buras, JA ;
Holzmann, B ;
Sitkovsky, M .
NATURE REVIEWS DRUG DISCOVERY, 2005, 4 (10) :854-865
[7]   Identification of resolvin D2 receptor mediating resolution of infections and organ protection [J].
Chiang, Nan ;
Dalli, Jesmond ;
Colas, Romain A. ;
Serhan, Charles N. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2015, 212 (08) :1203-1217
[8]   Infection regulates pro-resolving mediators that lower antibiotic requirements [J].
Chiang, Nan ;
Fredman, Gabrielle ;
Backhed, Fredrik ;
Oh, Sungwhan F. ;
Vickery, Thad ;
Schmidt, Birgitta A. ;
Serhan, Charles N. .
NATURE, 2012, 484 (7395) :524-U152
[9]   Resolvin D1 and Resolvin D2 Govern Local Inflammatory Tone in Obese Fat [J].
Claria, Joan ;
Dalli, Jesmond ;
Yacoubian, Stephanie ;
Gao, Fei ;
Serhan, Charles N. .
JOURNAL OF IMMUNOLOGY, 2012, 189 (05) :2597-2605
[10]   Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue [J].
Colas, Romain A. ;
Shinohara, Masakazu ;
Dalli, Jesmond ;
Chiang, Nan ;
Serhan, Charles N. .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2014, 307 (01) :C39-C54