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Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
Published on: June 7, 2017
Deletion of macrophage Gpr101 disrupts their phenotype and function dysregulating host immune responses in sterile
Magdalena B Flak1, Duco S Koenis2, Maria Gonzalez-Nunez2
1Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, UK.
Abstract:
We recently found that the G protein coupled receptor GPR101 mediates the phagocyte-directed pro-resolving activities of RvD5n-3 DPA (n-3 docosapentaenoic acid-derived Resolvin D5). Herein, we investigated the endogenous role of this pro-resolving receptor in modulating macrophage biology using a novel mouse line where the expression of Gpr101 was conditionally deleted in macrophages (MacGpr101KO). Peritoneal macrophages obtained from naïve MacGpr101KO mice displayed a marked shift in the expression of phenotypic and activation markers, including the Interleukin (IL)-10 and IL-23 receptors. Loss of Gpr101 on macrophages was also associated with a significant disruption in their cellular metabolism and a decreased ability to migrate towards the chemoattractant Mcp-1. The alterations in macrophage phenotype observed in Gpr101 deficient macrophages were maintained following inflammatory challenge. This was linked with an increased inflammatory response in the Gpr101 deficient animals and a reduced ability of phagocytes, including macrophages, to clear bacteria. Loss of Gpr101 on macrophages disrupted host pro-resolving responses to zymosan challenge with MacGpr101KO mice exhibiting significantly higher neutrophil numbers and a delay in the resolution interval when compared with control mice. These observations were linked with a marked dysregulation in peritoneal lipid mediator concentrations in Gpr101 deficient mice, with a downregulation of pro-resolving mediators including MaR2n-3 DPA, Resolvin (Rv) D3 and RvE3. Together these findings identify Gpr101 as a novel regulator of both macrophage phenotype and function, modulating key biological activities in both limiting the propagation of inflammation and expediting its resolution.
Insights
G protein coupled receptor GPR101 regulates macrophage function and inflammation resolution. Deleting GPR101 in macrophages impairs their metabolism, migration, and bacterial clearance, hindering the resolution of inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- G protein-coupled receptor 101 (GPR101) mediates pro-resolving activities of Resolvin D5 (RvD5) derived from n-3 docosapentaenoic acid (n-3 DPA).
- Understanding the endogenous role of GPR101 in macrophage biology is crucial for inflammatory disease research.
Purpose of the Study:
- To investigate the endogenous role of GPR101 in modulating macrophage phenotype and function.
- To determine the impact of GPR101 deficiency in macrophages on inflammatory responses and resolution.
Main Methods:
- Generation of a novel mouse line with conditional deletion of Gpr101 in macrophages (MacGpr101KO).
- Analysis of peritoneal macrophage phenotype, activation markers (IL-10, IL-23 receptors), cellular metabolism, and migration (Mcp-1).
- Assessment of inflammatory and pro-resolving responses following zymosan challenge, including neutrophil infiltration and lipid mediator concentrations.
Main Results:
- Naïve MacGpr101KO macrophages exhibited altered phenotypic and activation markers, disrupted metabolism, and reduced migration.
- Gpr101 deficiency led to increased inflammation, impaired bacterial clearance by phagocytes, and delayed resolution of inflammation after zymosan challenge.
- Peritoneal lipid mediator profiles were dysregulated in MacGpr101KO mice, with downregulation of pro-resolving mediators like MaR2n-3 DPA, RvD3, and RvE3.
Conclusions:
- GPR101 is a novel regulator of macrophage phenotype and function.
- GPR101 plays a critical role in limiting inflammatory propagation and expediting inflammation resolution.
- Targeting GPR101 may offer therapeutic strategies for inflammatory and resolution disorders.
