title: FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages.
abstract: FAM19A4 is an abbreviation for family with sequence similarity 19 (chemokine (C-C motif)-like) member A4, which is a secretory protein expressed in low levels in normal tissues. The biological functions of FAM19A4 remain to be determined, and its potential receptor(s) is unclarified. In this study, we demonstrated that FAM19A4 was a classical secretory protein and we verified for the first time that its mature protein is composed of 95 amino acids. We found that the expression of this novel cytokine was upregulated in lipopolysaccharide (LPS)-stimulated monocytes and macrophages and was typically in polarized M1. FAM19A4 shows chemotactic activities on macrophages and enhances the macrophage phagocytosis of zymosan both in vitro and in vivo with noticeable increases of the phosphorylation of protein kinase B (Akt). FAM19A4 can also increase the release of reactive oxygen species (ROS) upon zymosan stimulation. Furthermore, based on receptor internalization, radio ligand binding assays and receptor blockage, we demonstrated for the first time that FAM19A4 is a novel ligand of formyl peptide receptor 1 (FPR1). The above data indicate that upon inflammatory stimulation, monocyte/macrophage-derived FAM19A4 may play a crucial role in the migration and activation of macrophages during pathogenic infections.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Wanxiong
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Heyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Enquan
authors.initials: E
authors.lastname: Xu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Dalong
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; Peking University Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Wenling
authors.initials: W
authors.lastname: Han
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008024:Ligands; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009000:Monocytes / Q000473:pathology; D010587:Phagocytosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D008024:Ligands; D044042:Receptors, Formyl Peptide; C000607939:TAFA4 protein, human; D051057:Proto-Oncogene Proteins c-akt
references.citation: J Orthop Trauma. 2010 Sep;24(9):534-8
references.pmid: 20736789
references.citation: Adv Immunol. 2013;120:163-84
references.pmid: 24070384
references.citation: Cell Host Microbe. 2013 Sep 11;14(3):318-28
references.pmid: 24034617
references.citation: J Immunol. 2004 Feb 1;172(3):1896-906
references.pmid: 14734775
references.citation: Nat Immunol. 2011 Oct 19;12(11):1035-44
references.pmid: 22012443
references.citation: Nat Immunol. 2009 Apr;10(4):333-9
references.pmid: 19295629
references.citation: Pharmacol Rev. 2013 May 17;65(3):967-86
references.pmid: 23686350
references.citation: Annu Rev Pathol. 2012;7:61-98
references.pmid: 21910624
references.citation: Pharmacol Rev. 2009 Jun;61(2):119-61
references.pmid: 19498085
references.citation: Trends Immunol. 2002 Nov;23(11):541-8
references.pmid: 12401407
references.citation: PLoS One. 2011;6(5):e19651
references.pmid: 21603600
references.citation: Nature. 2010 Mar 4;464(7285):104-7
references.pmid: 20203610
references.citation: Biochemistry. 1991 May 21;30(20):5066-75
references.pmid: 1645188
references.citation: PLoS One. 2012;7(11):e50195
references.pmid: 23185575
references.citation: Sci Rep. 2012;2:786
references.pmid: 23139859
references.citation: J Immunol. 2014 Feb 15;192(4):1878-86
references.pmid: 24442440
references.citation: Genomics. 2004 Apr;83(4):727-34
references.pmid: 15028294
references.citation: Int Immunopharmacol. 2012 Nov;14(3):283-8
references.pmid: 22863814
references.citation: J Hepatol. 2013 Sep;59(3):583-94
references.pmid: 23567086
references.citation: FASEB J. 2007 Apr;21(4):1037-46
references.pmid: 17218541
references.citation: J Clin Invest. 2013 Jan;123(1):443-54
references.pmid: 23241962
references.citation: PLoS One. 2008 Oct 06;3(10):e3331
references.pmid: 18836528
references.citation: Curr Med Chem. 2014;21(13):1478-504
references.pmid: 24350845
references.citation: Cell Rep. 2013 Oct 31;5(2):378-88
references.pmid: 24139797
references.citation: Inflammation. 2007 Dec;30(6):224-9
references.pmid: 17687636
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2574-9
references.pmid: 20133797
references.citation: J Immunol. 2004 Jun 15;172(12):7669-76
references.pmid: 15187149
references.citation: Immunity. 2014 Feb 20;40(2):274-88
references.pmid: 24530056
references.citation: Nat Med. 2002 Nov;8(11):1296-302
references.pmid: 12368905
references.citation: Cell Immunol. 2012 Jul-Aug;278(1-2):136-42
references.pmid: 22960280
references.citation: Nat Rev Immunol. 2008 Apr;8(4):279-89
references.pmid: 18340345
references.citation: J Exp Med. 1998 Jun 15;187(12):2103-8
references.pmid: 9625771
references.citation: Cell Host Microbe. 2014 Apr 9;15(4):494-505
references.pmid: 24721577
references.citation: Nat Chem Biol. 2009 Jul;5(7):484-93
references.pmid: 19465931
references.citation: Nat Rev Mol Cell Biol. 2012 Dec;13(12):780-8
references.pmid: 23175281
references.citation: J Leukoc Biol. 2001 Jun;69(6):1045-52
references.pmid: 11404393
references.citation: J Immunol. 2001 Dec 1;167(11):6453-61
references.pmid: 11714812
references.citation: J Trauma. 2010 Jun;68(6):1328-32; discussion 1332-4
references.pmid: 20539176
references.citation: Cell Tissue Res. 1998 Apr;292(1):129-35
references.pmid: 9506920