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Formyl peptide receptor 2 is an emerging modulator of inflammation in the liver

정영미|Lee Chanbin|Han Jinsol
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2023.12|Experimental and Molecular Medicine|제55권 |pp. 325-332|DOI 10.1038/s12276-023-00941-1

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초록

Formyl peptide receptors (FPRs), which are seven-membrane G-protein coupled receptors, recognize chemotactic signals to protect hosts from pathogenic infections and mediate inflammatory responses in the body. There are three isoforms of FPRs in humans—FPR1, FPR2, and FPR3—and they bind to N-formyl peptides, except FPR3, and to various endogenous agonists. Among FPR family members, FPR2 has a lower affinity for N-formyl peptides than FPR1 and binds with a wide range of endogenous or exogenous agonists. Thus, FPR2 is considered the most ambiguous member. Accumulating evidence has shown that FPR2 is involved in the host’s defense against bacterial infection and inflammation in liver diseases, such as nonalcoholic fatty liver disease, liver fibrosis, and liver cancer, suggesting the pathophysiological relevance of FPR2 to the liver. However, FPR2 has been shown to promote or suppress inflammation, depending on the type of FPR2-expressing cell and FPR2-bound ligands in the liver. Therefore, it is important to understand FPR2’s function per se and to elucidate the mechanism underlying immunomodulation initiated by ligand-activated FPR2 before suggesting FPR2 as a novel therapeutic agent for liver diseases. In this review, up-to-date knowledge of FPR2, with general information on the FPR family, is provided. We shed light on the dual action of FPR2 in the liver and discuss the hepatoprotective roles of FPR2 itself and FPR2 agonists in mediating anti-inflammatory responses.

Abstract

Formyl peptide receptors (FPRs), which are seven-membrane G-protein coupled receptors, recognize chemotactic signals to protect hosts from pathogenic infections and mediate inflammatory responses in the body. There are three isoforms of FPRs in humans—FPR1, FPR2, and FPR3—and they bind to N-formyl peptides, except FPR3, and to various endogenous agonists. Among FPR family members, FPR2 has a lower affinity for N-formyl peptides than FPR1 and binds with a wide range of endogenous or exogenous agonists. Thus, FPR2 is considered the most ambiguous member. Accumulating evidence has shown that FPR2 is involved in the host’s defense against bacterial infection and inflammation in liver diseases, such as nonalcoholic fatty liver disease, liver fibrosis, and liver cancer, suggesting the pathophysiological relevance of FPR2 to the liver. However, FPR2 has been shown to promote or suppress inflammation, depending on the type of FPR2-expressing cell and FPR2-bound ligands in the liver. Therefore, it is important to understand FPR2’s function per se and to elucidate the mechanism underlying immunomodulation initiated by ligand-activated FPR2 before suggesting FPR2 as a novel therapeutic agent for liver diseases. In this review, up-to-date knowledge of FPR2, with general information on the FPR family, is provided. We shed light on the dual action of FPR2 in the liver and discuss the hepatoprotective roles of FPR2 itself and FPR2 agonists in mediating anti-inflammatory responses.

참고문헌 (94)

  1. Chen, L., "Inflammatory responses and inflammation-associated diseases in organs", Oncotarget, 9, pp.7204~7218 (2018)
  2. Medzhitov, R., "Origin and physiological roles of inflammation", Nature, 454, pp.428~435 (2008)
  3. Kanneganti, T. D., "Innate immune pathways in host defense", Mediators Inflamm, 2012, pp.708972~ (2012)
  4. Liaskou, E., "Innate immune cells in liver inflammation", Mediators Inflamm, 2012, pp.949157~ (2012)
  5. Seki, S., "The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1immune responses", Immunol. Rev, 174, pp.35~46 (2000)
  6. Czaja, A. J., "Hepatic inflammation and progressive liver fibrosis in chronic liver disease", World J. Gastroenterol, 20, pp.2515~2532 (2014)
  7. Seki, E., "Hepatic inflammation and fibrosis: functional links and key pathways", Hepatology, 61, pp.1066~1079 (2015)
  8. Del Campo, J. A., "Role of inflammatory response in liver diseases : therapeutic strategies", World J. Hepatol, 10, pp.1~7 (2018)
  9. Amarante-Mendes, G. P., "Pattern recognition receptors and the host cell death molecular machinery", Front. Immunol, 9, pp.2379~ (2018)
  10. Schiffmann, E., "N-formylmethionyl peptides as chemoattractants for leucocytes", Proc. Natl Acad. Sci. USA, 72, pp.1059~1062 (1975)
  11. Tian, C., "The G-protein coupled formyl peptide receptors and their role in the progression of digestive tract cancer", Technol. Cancer Res. Treat, 19, pp.1533033820973280~ (2020)
  12. Tylek, K., "Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation : a link to brain pathology", Pharmacol. Rep, 73, pp.1004~1019 (2021)
  13. Ye, R. D., "International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family", Pharmacol. Rev, 61, pp.119~161 (2009)
  14. Petri, M. H., "The role of the FPR2", ALX receptor in atherosclerosis development and plaque stability, 2015, pp.105, 65~74
  15. Yu, Y., "The G-protein-coupled chemoattractant receptor Fpr2 exacerbates neuroglial dysfunction and angiogenesis in diabetic retinopathy", FASEB Bioadv, 2, pp.613~623 (2020)
  16. Oldekamp, S., "Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of pneumococcal meningitis", Immunology, 143, pp.447~461 (2014)
  17. Kim, H., "LXA(4)-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β", Smad signaling, 2020, pp.11, 653~
  18. Sun, Z., "Fpr2", CXCL1, Front. Immunol, pp.2021, 12[DOI]
  19. Liu, M., "Formylpeptide receptors are critical for rapid neutrophil mobilization in host defense against Listeria monocytogenes", Sci. Rep, 2, pp.786~ (2012)
  20. Kang, J. W., "Resolvin D1 activates the sphingosine-1-phosphate signaling pathway in murine livers with ischemia", reperfusion injury, 2019, pp.514, 1058~1065
  21. Kang, J. W., "Resolvin D1 attenuates liver ischaemia", reperfusion injury through modulating thioredoxin 2-mediated mitochondrial quality control, 2018, pp.175, 2441~2453
  22. Xu, F., "Lipoxin A(4)and its analog suppress hepatocarcinoma cell epithelialmesenchymal transition, migration and metastasis via regulating integrin-linked kinase axis", Prostaglandins Other Lipid Mediat, 137, pp.9~19 (2018)
  23. Lee, C., "Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis", Nat. Commun, 13, pp.578~ (2022)
  24. Chen, X., "Fpr2 deficiency alleviates diet-induced insulin resistance through reducing body weight gain and inhibiting inflammation mediated by macrophage chemotaxis and M1 polarization", Diabetes, 68, pp.1130~1142 (2019)
  25. Weiß, E., "Formyl-peptide receptors in infection, inflammation, and cancer", Trends Immunol, 39, pp.815~829 (2018)
  26. Panaro, M. A., "Formyl peptide receptors on immune and nonimmune cells : analysis of sequence conservation in FPR genes", Immunopharmacol. Immunotoxicol, 29, pp.243~269 (2007)
  27. Migeotte, I., "Formyl peptide receptors : a promiscuous subfamily of G protein-coupled receptors controlling immune responses", Cytokine Growth Factor Rev, 17, pp.501~519 (2006)
  28. He, H. Q., "The formyl peptide receptors: diversity of ligands and mechanism for recognition", Molecules, 22, pp.455~ (2017)
  29. Gao, J. L., "Differential expansion of the N-formylpeptide receptor gene cluster in human and mouse", Genomics, 51, pp.270~276 (1998)
  30. Hartt, J. K., "N-formylpeptides induce two distinct concentration optima for mouse neutrophil chemotaxis by differential interaction with two N-formylpeptide receptor (FPR) subtypes. Molecular characterization of FPR2, a second mouse neutrophil FPR", J. Exp. Med, 190, pp.741~747 (1999)
  31. Chen, K., "Regulation of inflammation by members of the formyl-peptide receptor family", J. Autoimmun, 85, pp.64~77 (2017)
  32. Gao, J. L., "F2L, a peptide derived from heme-binding protein, chemoattracts mouse neutrophils by specifically activating Fpr2, the low-affinity N-formylpeptide receptor", J. Immunol, 178, pp.1450~1456 (2007)
  33. Migeotte, I., "Identification and characterization of an endogenous chemotactic ligand specific for FPRL2", J. Exp. Med, 201, pp.83~93 (2005)
  34. Yang, D., "Differential regulation of formyl peptide receptor-like 1 expression during the differentiation of monocytes to dendritic cells and macrophages", J. Immunol, 166, pp.4092~4098 (2001)
  35. Kim, S. D., "Functional expression of formyl peptide receptor family in human NK cells", J. Immunol, 183, pp.5511~5517 (2009)
  36. Devosse, T., "Formyl peptide receptor-like 2 is expressed and functional in plasmacytoid dendritic cells, tissue-specific macrophage subpopulations, and eosinophils", J. Immunol, 182, pp.4974~4984 (2009)
  37. Prossnitz, E. R., "The N-formyl peptide receptor : a model for the study of chemoattractant receptor structure and function", Pharmacol. Ther, 74, pp.73~102 (1997)
  38. Ye, R. D., "Isolation of a cDNA that encodes a novel granulocyte N-formyl peptide receptor", Biochem. Biophys. Res. Commun, 184, pp.582~589 (1992)
  39. 박유정, "Promotion of formyl peptide receptor 1-mediated neutrophil chemotactic migration by antimicrobial peptides isolated from the centipede Scolopendra subspinipes mutilans", BMB Reports, 49(9), pp.520~525 (2016), 생화학분자생물학회
  40. Kretschmer, D., "Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus", Cell Host Microbe, 7, pp.463~473 (2010)
  41. Seki, T., "Mitocryptide-2, a neutrophil-activating cryptide, is a specific endogenous agonist for formyl-peptide receptor-like 1", Biochem. Biophys. Res. Commun, 404, pp.482~487 (2011)
  42. He, H. Q., "Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands", J. Biol. Chem, 289, pp.2295~2306 (2014)
  43. Sun, R., "Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor", J. Immunol, 173, pp.428~436 (2004)
  44. He, R., "Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1", LXA4R, 2003, pp.101, 1572~1581
  45. Nagaoka, I., "An antimicrobial cathelicidin peptide, human CAP18", LL-37, suppresses neutrophil apoptosis via the activation of formylpeptide receptor-like 1 and P2X7, 2006, pp.176, 3044~3052
  46. Luo, B., "Resolvin D1 programs inflammation resolution by increasing TGF-βexpression induced by dying cell clearance in experimental autoimmune neuritis", J. Neurosci, 36, pp.9590~9603 (2016)
  47. Prieto, P., "Lipoxin A4 impairment of apoptotic signaling in macrophages : implication of the PI3K", Akt and the ERK, Cell Death Differ, pp.2010, 17[DOI]
  48. Cooray, S. N., "Ligand-specific conformational change of the G-proteincoupled receptor ALX", FPR2 determines proresolving functional responses, 2013, pp.110, 18232~18237
  49. Bena, S., "Annexin A1interaction with the FPR2", ALX receptor : identification of distinct domains and downstream associated signaling, 2012, pp.287, 24690~24697
  50. Ye, R. D., "Emerging functions of serum amyloid A in inflammation", J. Leukoc. Biol, 98, pp.923~929 (2015)
  51. El Kebir, D., "Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation", Proc. Natl Acad. Sci. USA, 109, pp.14983~14988 (2012)
  52. Lee, H. Y., "Serum amyloid A stimulates matrix-metalloproteinase-9 upregulation via formyl peptide receptor like-1-mediated signaling in human monocytic cells", Biochem. Biophys. Res. Commun, 330, pp.989~998 (2005)
  53. Tiffany, H. L., "Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2, a G protein-coupled receptor expressed in phagocytes and brain", J. Biol. Chem, 276, pp.23645~23652 (2001)
  54. Zhu, Y., "Structural basis of FPR2 in recognition of Aβ(42)and neuroprotection by humanin", Nat. Commun, 13, pp.1775~ (2022)
  55. Gouwens, L. K, "Amyloid-β42 protofibrils are internalized by microglia more extensively than monomers", Brain Res, 1648, pp.485~495 (2016)
  56. Ying, G., "Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor", J. Immunol, 172, pp.7078~7085 (2004)
  57. Le, Y., "The neurotoxic prion peptide fragment PrP(106-126)is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1", J. Immunol, 166, pp.1448~1451 (2001)
  58. van der Does, A. M., "LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature", J. Immunol, 185, pp.1442~1449 (2010)
  59. Serhan, C. N., "Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution", Prostaglandins Leukot. Essent. Fat. Acids, 73, pp.141~162 (2005)
  60. Chiang, N., "Activation of lipoxin A(4)receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation", J. Exp. Med, 191, pp.1197~1208 (2000)
  61. Dufton, N., "Therapeutic anti-inflammatory potential of formylpeptide receptor agonists", Pharmacol. Ther, 127, pp.175~188 (2010)
  62. Maderna, P., "FPR2", ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis, 2010, pp.24, 4240~4249
  63. Serhan, C. N., "Resolving inflammation : dual antiinflammatory and pro-resolution lipid mediators", Nat. Rev. Immunol, 8, pp.349~361 (2008)
  64. Serhan, C. N., "Resolution phase of inflammation : novel endogenous antiinflammatory and proresolving lipid mediators and pathways", Annu. Rev. Immunol, 25, pp.101~137 (2007)
  65. Serhan, C. N., "Resolvins : a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals", J. Exp. Med, 196, pp.1025~1037 (2002)
  66. Krishnamoorthy, S., "Resolvin D1 binds human phagocytes with evidence for proresolving receptors", Proc. Natl Acad. Sci. USA, 107, pp.1660~1665 (2010)
  67. Li, A., "Effect of RvD1", FPR2 on inflammatory response in chorioamnionitis, 2020, pp.24, 13397~13407
  68. Liao, Z., "Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPARγ", NF-κB pathway, 2012, pp.13, 110~
  69. Perretti, M., "Endogenous lipid-and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor", Nat. Med, 8, pp.1296~1302 (2002)
  70. Rüger, M., "The formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis", J. Neuroinflammation, 17, pp.325~ (2020)
  71. Zhang, M., "A critical role of formyl peptide receptors in host defense against Escherichia coli", J. Immunol, 204, pp.2464~2473 (2020)
  72. Giebeler, A., "Deficiency of formyl peptide receptor 1 and 2 is associated with increased inflammation and enhanced liver injury after LPS-stimulation", PLoS ONE, 9, pp.e100522~ (2014)
  73. Vilar-Gomez, E., "Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease : a multi-national cohort study", Gastroenterology, 155, pp.443~457 (2018)
  74. Lonardo, A., "Sex differences in nonalcoholic fatty liver disease : state of the art and identification of research gaps", Hepatology, 70, pp.1457~1469 (2019)
  75. Sugasawa, T., "One week of CDAHFD induces steatohepatitis and mitochondrial dysfunction with oxidative stress in liver", Int. J. Mol. Sci, 22, pp.5851~ (2021)
  76. Matsumoto, M., "An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis", Int. J. Exp. Pathol, 94, pp.93~103 (2013)
  77. Gupte, A. A., "High-fat feeding-induced hyperinsulinemia increases cardiac glucose uptake and mitochondrial function despite peripheral insulin resistance", Endocrinology, 154, pp.2650~2662 (2013)
  78. Zhang, X., "New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD)", Protein Cell, 9, pp.164~177 (2018)
  79. Murakami, T., "Suppressive action of resolvin D1 on the production and release of septic mediators in D-galactosaminesensitized endotoxin shock mice", Exp. Ther. Med, 2, pp.57~61 (2011)
  80. Kang, J. W., "Resolvin D1 protects the liver from ischemia", reperfusion injury by enhancing M2 macrophage polarization and efferocytosis, 2016, pp.1861, 1025~1035
  81. Jiang, X., "Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway", Int. J. Mol. Med, 37, pp.773~780 (2016)
  82. Börgeson, E., "Lipoxin A4 attenuates obesity-induced adipose inflammation and associated liver and kidney disease", Cell Metab, 22, pp.125~137 (2015)
  83. Rius, B., "Resolvin D1 primes the resolution process initiated by calorie restriction in obesity-induced steatohepatitis", FASEB J, 28, pp.836~848 (2014)
  84. Li, J., "Resolvin D1 mitigates non-alcoholic steatohepatitis by suppressing the TLR4-MyD88-mediated NF-κB and MAPK pathways and activating the Nrf2pathway in mice", Int. Immunopharmacol, 88, pp.106961~ (2020)
  85. Purvis, G. S. D., "Identification of AnnexinA1 as an endogenous regulator of RhoA, and its role in the pathophysiology and experimental therapy of type-2diabetes", Front. Immunol, 10, pp.571~ (2019)
  86. Locatelli, I., "Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice", Hepatology, 60, pp.531~544 (2014)
  87. Li, Q., "HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK", ERK and PI3K, J. Exp. Clin. Cancer Res, pp.2018, 37[DOI]
  88. Hao, H., "Lipoxin A4 and its analog suppress hepatocellular carcinoma via remodeling tumor microenvironment", Cancer Lett, 309, pp.85~94 (2011)
  89. Chen, Y., "Lipoxin A4 and its analogue suppress the tumor growth of transplanted H22 in mice : the role of antiangiogenesis", Mol. Cancer Ther, 9, pp.2164~2174 (2010)
  90. Jun, J. H., "Formyl peptide receptor 2 alleviates hepatic fibrosis in liver cirrhosis by vascular remodeling", Int. J. Mol. Sci, 22, pp.2107~ (2021)
  91. Jun, J. H., "Combination therapy of placenta-derived mesenchymal stem cells with WKYMVm promotes hepatic function in a rat model with hepatic disease via vascular remodeling", Cells, 11, pp.232~ (2022)
  92. Cattaneo, F., "WKYMVm-induced cross-talk between FPR2 and HGF receptor in human prostate epithelial cell line PNT1A", FEBS Lett, 587, pp.1536~1542 (2013)
  93. Getachew, A., "SAA1", TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury, 2021, pp.24, 102483~
  94. El-Agamy, D. S., "Protective effects of BML-111 against acetaminophen-induced acute liver injury in mice", J. Physiol. Biochem, 70, pp.141~149 (2014)

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