{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Formyl peptide receptor 2 (FPR2), also known as FPR‐like 1 (FPRL1) or ALX, is a versatile G protein–coupled receptor expressed on a range of immune and nonimmune cells – including neutrophils, monocytes, macrophages, endothelial cells, and even certain epithelial cell types – that orchestrates both proinflammatory and proresolving responses. Activation of FPR2 by multiple endogenous ligands such as the antimicrobial peptide LL‐37 has been shown to promote angiogenesis and endothelial activation, thereby contributing to wound healing and tissue repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, engagement of FPR2 by serum amyloid A (SAA) leads to NF‐κB activation and subsequent proinflammatory cytokine (eg, IL‐8) production, highlighting its role in amplifying inflammation in certain settings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond driving inflammation, FPR2 signaling also underlies crucial resolution mechanisms. For example, apoptotic cell–derived factors acting via FPR2 facilitate macrophage efferocytosis, thereby ensuring a timely clearance of dying cells and promoting the resolution of inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similarly, FPR2 mediates the chemotactic recruitment of mesenchymal stem cells into tumor microenvironments, a process that influences both neovascularization and stromal remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of leukocyte trafficking, FPR2 activation by cathelicidins such as LL‐37 or its murine homologue CRAMP directs the chemotaxis of monocytes and neutrophils via integrin conformational changes and clustering, thereby facilitating efficient cellular adhesion and migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural and pharmacologic studies have further delineated key extracellular and transmembrane domains in FPR2 that determine ligand specificity and downstream signaling bias, allowing FPR2 to mediate opposing signals – from promoting inflammatory cytokine production to triggering anti‐inflammatory and resolving cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, FPR2 engagement has been implicated in the modulation of matrix metalloproteinase expression and cell survival in inflammatory arthritis, where SAA–FPR2 interactions can stimulate synoviocyte proliferation and matrix degradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In vascular contexts, the activation of this receptor by annexin A1–derived peptides can attenuate leukocyte integrin activation, thereby reducing arterial leukocyte adhesion and influencing atherosclerotic lesion formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the pleiotropic role of FPR2 as a critical regulator of host defense mechanisms, immune cell recruitment, tissue repair, and the resolution of inflammation.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rembert Koczulla, Georges von Degenfeld, Christian Kupatt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An angiogenic role for the human peptide antibiotic LL-37/hCAP-18."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI17545"}], "href": "https://doi.org/10.1172/JCI17545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12782669"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12782669"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Rong He, Hairong Sang, Richard D Ye "}, {"type": "b", "children": [{"type": "t", "text": "Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2002-05-1431"}], "href": "https://doi.org/10.1182/blood-2002-05-1431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12393391"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12393391"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Michael Scannell, Michelle B Flanagan, Andreas deStefani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Annexin-1 and peptide derivatives are released by apoptotic cells and stimulate phagocytosis of apoptotic neutrophils by macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.178.7.4595"}], "href": "https://doi.org/10.4049/jimmunol.178.7.4595"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17372018"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17372018"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Seth B Coffelt, Frank C Marini, Keri Watson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0900244106"}], "href": "https://doi.org/10.1073/pnas.0900244106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19234121"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19234121"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Isao Nagaoka, Hiroshi Tamura, Michimasa Hirata "}, {"type": "b", "children": [{"type": "t", "text": "An antimicrobial cathelicidin peptide, human CAP18/LL-37, suppresses neutrophil apoptosis via the activation of formyl-peptide receptor-like 1 and P2X7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.176.5.3044"}], "href": "https://doi.org/10.4049/jimmunol.176.5.3044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16493063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16493063"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sarawuth Wantha, Jean-Eric Alard, Remco T A Megens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neutrophil-derived cathelicidin promotes adhesion of classical monocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.112.300666"}], "href": "https://doi.org/10.1161/CIRCRESAHA.112.300666"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23283724"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23283724"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Stefania Bena, Vincenzo Brancaleone, Ji Ming Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Annexin A1 interaction with the FPR2/ALX receptor: identification of distinct domains and downstream associated signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.377101"}], "href": "https://doi.org/10.1074/jbc.M112.377101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22610094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22610094"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Anna-Lena Stenfeldt, Jennie Karlsson, Christine Wennerås, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclosporin H, Boc-MLF and Boc-FLFLF are antagonists that preferentially inhibit activity triggered through the formyl peptide receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Inflammation (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10753-007-9040-4"}], "href": "https://doi.org/10.1007/s10753-007-9040-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17687636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17687636"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ethan P Grant, Dominic Picarella, Timothy Burwell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20020205"}], "href": "https://doi.org/10.1084/jem.20020205"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12461081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12461081"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mi-Sook Lee, Seung-Ah Yoo, Chul-Soo Cho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum amyloid A binding to formyl peptide receptor-like 1 induces synovial hyperplasia and angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.177.8.5585"}], "href": "https://doi.org/10.4049/jimmunol.177.8.5585"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17015746"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17015746"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Maik Drechsler, Renske de Jong, Jan Rossaint, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.116.305825"}], "href": "https://doi.org/10.1161/CIRCRESAHA.116.305825"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25520364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25520364"}]}]}]}