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      Defective formyl peptide receptor 2/3 and annexin A1 expressions associated with M2a polarization of blood immune cells in patients with chronic obstructive pulmonary disease

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          Abstract

          Background

          Controversy exists in previous studies on macrophage M1/M2 polarization in chronic obstructive pulmonary disease (COPD). We hypothesized that formyl peptide receptor (FPR), a marker of efferocytosis and mediator of M1/M2 polarization, may be involved in the development of COPD.

          Methods

          We examined FPR 1/2/3 expressions of blood M1/M2a monocyte, neutrophil, natural killer (NK) cell, NK T cell, T helper (Th) cell, and T cytotoxic (Tc) cell by flowcytometry method in 40 patients with cigarette smoking-related COPD and 16 healthy non-smokers. Serum levels of five FPR ligands were measured by ELISA method.

          Results

          The COPD patients had lower M2a percentage and higher percentages of NK, NK T, Th, and Tc cells than the healthy non-smokers. FPR2 expressions on Th/Tc cells, FPR3 expressions of M1, M2a, NK, NK T, Th, and Tc cells, and serum annexin A1 (an endogenous FPR2 ligand) levels were all decreased in the COPD patients as compared with that in the healthy non-smokers. FPR1 expression on neutrophil was increased in the COPD patient with a high MMRC dyspnea scale, while FPR2 expression on neutrophil and annexin A1 were both decreased in the COPD patients with a history of frequent moderate exacerbation (≥ 2 events in the past 1 year). In 10 COPD patients whose blood samples were collected again after 1-year treatment, M2a percentage, FPR3 expressions of M1/NK/Th cells, FPR2 expression on Th cell, and FPR1 expression on neutrophil were all reversed to normal, in parallel with partial improvement in small airway dysfunction.

          Conclusions

          Our findings provide evidence for defective FPR2/3 and annexin A1 expressions that, associated with decreased M2a polarization, might be involved in the development of cigarette smoking induced persistent airflow limitation in COPD.

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          Most cited references32

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          Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease.

          When exposed to a specific microenvironment, macrophages acquire either M1- or M2-polarized phenotypes associated with inflammation and tissue remodeling, respectively. Alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for chronic obstructive pulmonary disease (COPD), a disease characterized by lung inflammation and remodeling. Transcriptional profiling of AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers, and 12 COPD smokers was performed to test the hypothesis whether smoking alters AM polarization, resulting in a disease-relevant activation phenotype. The analysis revealed that AM of healthy smokers exhibited a unique polarization pattern characterized by substantial suppression of M1-related inflammatory/immune genes and induction of genes associated with various M2-polarization programs relevant to tissue remodeling and immunoregulation. Such reciprocal changes progressed with the development of COPD, with M1-related gene expression being most dramatically down-regulated (p < 0.0001 vs healthy nonsmokers, p < 0.002 vs healthy smokers). Results were confirmed with TaqMan real-time PCR and flow cytometry. Among progressively down-regulated M1-related genes were those encoding type I chemokines CXCL9, CXCL10, CXCL11, and CCL5. Progressive activation of M2-related program was characterized by induction of tissue remodeling and immunoregulatory genes such as matrix metalloproteinase (MMP)2, MMP7, and adenosine A3 receptor (ADORA3). Principal component analysis revealed that differential expression of polarization-related genes has substantial contribution to global AM phenotypes associated with smoking and COPD. In summary, the data provide transcriptome-based evidence that AM likely contribute to COPD pathogenesis in a noninflammatory manner due to their smoking-induced reprogramming toward M1-deactivated, partially M2-polarized macrophages.
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            Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.

            N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1(-/-IEC) and AnxA1(-/-) mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.
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              The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation.

              Neutrophil migration to sites of inflammation and the subsequent execution of multiple functions are designed to contain and kill invading pathogens. These highly regulated and orchestrated processes are controlled by interactions between numerous receptors and their cognate ligands. Unraveling and identifying those that are central to inflammatory processes may represent novel therapeutic targets for the treatment of neutrophil-dominant inflammatory disorders in which dysregulated neutrophil recruitment, function, and elimination serve to potentiate rather than resolve an initial inflammatory insult. The first G protein-coupled receptor to be described on human neutrophils, formyl peptide receptor 1 (FPR1), is one such receptor that plays a significant role in the execution of these functions through multiple intracellular signaling pathways. Recent work has highlighted important observations with regard to both receptor function and the importance and functional relevance of FPR1 in the pathogenesis of a range of both sterile and infective inflammatory conditions. In this review, we explore the multiple components of neutrophil migration and function in both health and disease, with a focus on the role of FPR1 in these processes. The current understanding of FPR1 structure, function, and signaling is examined, alongside discussion of the potential importance of FPR1 in inflammatory diseases suggesting that FPR1 is a key regulator of the inflammatory environment.
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                Author and article information

                Contributors
                yungchechen@yahoo.com.tw
                +886-7-7317123 , linmengchih@hotmail.com
                dermlee@gmail.com
                m85d@adm.cgmh.org.tw
                ccwang5202@yahoo.com.tw
                wenfengfang@yahoo.com.tw
                tychao@adm.cgmh.org.tw
                my47104710@gmail.com
                yufeng528@gmail.com
                kuan2101@yahoo.com.tw
                cctseng@cgmh.org.tw
                chc1106@cgmh.org.tw
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                15 March 2018
                15 March 2018
                2018
                : 16
                : 69
                Affiliations
                [1 ]GRID grid.145695.a, Division of Pulmonary and Critical Care Medicine, , Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, ; Kaohsiung, Taiwan
                [2 ]GRID grid.145695.a, Medical Department, College of Medicine, , Chang Gung University, ; Taoyuan, Taiwan
                [3 ]GRID grid.145695.a, Department of Dermatology, , Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, ; Kaohsiung, Taiwan
                [4 ]GRID grid.145695.a, Department of Respiratory Therapy, , Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, ; Kaohsiung, Taiwan
                [5 ]GRID grid.418428.3, Chang Gung University of Science and Technology, ; Chia-yi, Taiwan
                [6 ]ISNI 0000 0004 0637 1806, GRID grid.411447.3, Department of Internal Medicine, E-Da Hospital, , I-Shou University, ; Kaohsiung, Taiwan
                [7 ]GRID grid.145695.a, Division of Pulmonary and Critical Care Medicine, Department of Medicine, , Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, ; 123, Ta-Pei Rd, Niao-Sung District, Kaohsiung, Taiwan
                Author information
                http://orcid.org/0000-0001-8695-5227
                Article
                1435
                10.1186/s12967-018-1435-5
                5856198
                29544524
                576a9e66-be5b-4f1f-8196-63c183cb6d11
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 June 2017
                : 5 March 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: 101-2325-B-002-064/ 102-2325-B-002-087/103-2325-B-002-027/ 104-2325-B-002-035/105-2325-B-002-030
                Award Recipient :
                Funded by: Chang Gung Memorial Hospital, Kaohsiung
                Award ID: CMRPG8D1571/CMRPG8D1572
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Medicine
                formyl peptide receptor 1/2/3,m2a polarization,chronic obstructive pulmonary disease,cigarette smoking,annexin a1

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