title: IL-17 promotes neutrophil entry into tumor-draining lymph nodes following induction of sterile inflammation.
abstract: Blood-borne neutrophils are excluded from entering lymph nodes across vascular portals termed high endothelial venules (HEVs) because of lack of expression of the CCR7 homeostatic chemokine receptor. Induction of sterile inflammation increases neutrophil entry into tumor-draining lymph nodes (TDLNs), which is critical for induction of antitumor adaptive immunity following treatments such as photodynamic therapy (PDT). However, the mechanisms controlling neutrophil entry into TDLNs remain unclear. Prior evidence that IL-17 promotes neutrophil emigration to sites of infection via induction of CXCL2 and CXCL1 inflammatory chemokines raised the question of whether IL-17 contributes to chemokine-dependent trafficking in TDLNs. In this article, we demonstrate rapid accumulation of IL-17-producing Th17 cells in the TDLNs following induction of sterile inflammation by PDT. We further report that nonhematopoietic expression of IL-17RA regulates neutrophil accumulation in TDLNs following induction of sterile inflammation by PDT. We show that HEVs are the major route of entry of blood-borne neutrophils into TDLNs through interactions of l-selectin with HEV-expressed peripheral lymph node addressin and by preferential interactions between CXCR2 and CXCL2 but not CXCL1. CXCL2 induction in TDLNs was mapped in a linear pathway downstream of IL-17RA-dependent induction of IL-1β. These results define a novel IL-17-dependent mechanism promoting neutrophil delivery across HEVs in TDLNs during acute inflammatory responses.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Brackett
authors.forename: Jason B
authors.initials: JB
authors.lastname: Muhitch
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Evans
authors.forename: Sandra O
authors.initials: SO
authors.lastname: Gollnick
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D019041:L-Selectin / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D010778:Photochemotherapy; D053722:Receptors, Interleukin-17 / Q000096:biosynthesis; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D053722:Receptors, Interleukin-17; D023063:Receptors, Interleukin-8B; D019041:L-Selectin
references.citation: Br J Cancer. 2003 Jun 2;88(11):1772-9
references.pmid: 12771994
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Apr;292(4):L1023-9
references.pmid: 17189320
references.citation: J Exp Med. 1998 Jan 19;187(2):205-16
references.pmid: 9432978
references.citation: Cell. 2007 Aug 24;130(4):691-703
references.pmid: 17719546
references.citation: Nat Rev Immunol. 2012 Nov;12(11):762-73
references.pmid: 23018291
references.citation: J Immunol. 1989 Nov 15;143(10):3318-24
references.pmid: 2553811
references.citation: Nat Rev Immunol. 2006 Mar;6(3):173-82
references.pmid: 16498448
references.citation: Nat Rev Immunol. 2003 Nov;3(11):867-78
references.pmid: 14668803
references.citation: J Clin Invest. 2011 Oct;121(10):3846-59
references.pmid: 21926464
references.citation: J Cell Biol. 1994 Apr;125(2):461-70
references.pmid: 7512970
references.citation: Am J Respir Cell Mol Biol. 2001 Sep;25(3):335-40
references.pmid: 11588011
references.citation: J Immunol. 2009 Aug 15;183(4):2330-6
references.pmid: 19620297
references.citation: Cancer Res. 2004 Mar 15;64(6):2120-6
references.pmid: 15026352
references.citation: Immunity. 2009 Jan 16;30(1):108-19
references.pmid: 19144317
references.citation: J Exp Med. 2000 Nov 20;192(10):1441-52
references.pmid: 11085746
references.citation: Cancer Res. 1997 Sep 15;57(18):3904-9
references.pmid: 9307269
references.citation: Cytokine. 2008 Feb;41(2):92-104
references.pmid: 18178098
references.citation: Nat Immunol. 2001 Aug;2(8):675-80
references.pmid: 11477402
references.citation: J Immunol. 2010 Apr 15;184(8):4447-54
references.pmid: 20220092
references.citation: J Exp Med. 2001 Nov 5;194(9):1361-73
references.pmid: 11696600
references.citation: Blood. 2010 Sep 16;116(11):1924-31
references.pmid: 20530797
references.citation: J Allergy Clin Immunol. 2000 Jan;105(1 Pt 1):143-9
references.pmid: 10629464
references.citation: J Immunol. 2012 Nov 1;189(9):4231-5
references.pmid: 23024281
references.citation: Atherosclerosis. 1995 May;115(1):89-98
references.pmid: 7545398
references.citation: Nat Rev Immunol. 2007 Jan;7(1):31-40
references.pmid: 17186029
references.citation: Immunol Rev. 2007 Dec;220:47-59
references.pmid: 17979839
references.citation: Nat Rev Immunol. 2010 Jul;10(7):479-89
references.pmid: 20559326
references.citation: J Immunol. 2005 Apr 15;174(8):4845-51
references.pmid: 15814711
references.citation: J Immunol. 2008 Feb 15;180(4):2545-52
references.pmid: 18250465
references.citation: Eur J Immunol. 2010 Mar;40(3):607-11
references.pmid: 20201012
references.citation: J Leukoc Biol. 2004 Apr;75(4):641-8
references.pmid: 14704366
references.citation: Annu Rev Immunol. 2010;28:321-42
references.pmid: 20307211
references.citation: J Immunol. 2010 Apr 15;184(8):4531-7
references.pmid: 20228195
references.citation: Nat Rev Immunol. 2009 Aug;9(8):556-67
references.pmid: 19575028
references.citation: Int Immunol. 2012 Mar;24(3):147-58
references.pmid: 22207130
references.citation: Photochem Photobiol Sci. 2011 May;10(5):670-80
references.pmid: 21258717
references.citation: Immunology. 2003 Apr;108(4):523-30
references.pmid: 12667214
references.citation: Immunity. 1995 Dec;3(6):811-21
references.pmid: 8777726
references.citation: J Biol Chem. 2011 Mar 4;286(9):7348-58
references.pmid: 21173151
references.citation: J Leukoc Biol. 2002 Nov;72(5):847-55
references.pmid: 12429706
references.citation: J Immunol. 2008 Mar 15;180(6):4308-15
references.pmid: 18322244
references.citation: Transplantation. 2004 Jan 15;77(1):115-21
references.pmid: 14724445
references.citation: Blood. 2011 Jan 27;117(4):1196-204
references.pmid: 21051556
references.citation: J Exp Med. 1994 Nov 1;180(5):1785-92
references.pmid: 7525838
references.citation: Shock. 2001 Apr;15(4):278-84
references.pmid: 11303726
references.citation: Front Immunol. 2012 Sep 28;3:305
references.pmid: 23060883
references.citation: Nat Immunol. 2005 May;6(5):497-506
references.pmid: 15834409
references.citation: J Immunol. 2010 Jul 15;185(2):1063-70
references.pmid: 20554964
references.citation: Immunity. 2008 Sep 19;29(3):487-96
references.pmid: 18718768
references.citation: Cancer Immunol Immunother. 2006 Mar;55(3):299-311
references.pmid: 16044255
references.citation: J Biol Chem. 2007 Feb 16;282(7):4812-4820
references.pmid: 17172469
references.citation: Eur J Immunol. 2006 Apr;36(4):968-76
references.pmid: 16541467
references.citation: Photochem Photobiol. 2001 Nov;74(5):712-20
references.pmid: 11723800
references.citation: J Exp Med. 2005 Apr 18;201(8):1281-92
references.pmid: 15837813
references.citation: Science. 2010 Oct 15;330(6002):362-6
references.pmid: 20947763
references.citation: Blood. 2005 Sep 1;106(5):1843-50
references.pmid: 15886329
references.citation: Nat Immunol. 2006 Dec;7(12):1299-308
references.pmid: 17086187
references.citation: Nat Rev Immunol. 2011 Jul 25;11(8):519-31
references.pmid: 21785456
references.citation: Blood. 2006 Nov 1;108(9):3094-102
references.pmid: 16835380
references.citation: Nat Rev Immunol. 2010 Dec;10(12):826-37
references.pmid: 21088683
references.citation: EMBO J. 1999 Dec 15;18(24):6962-72
references.pmid: 10601018
references.citation: Nat Immunol. 2009 Oct;10(10):1125-32
references.pmid: 19734905
references.citation: J Immunol. 2006 Jul 1;177(1):36-9
references.pmid: 16785495
references.citation: Cytokine. 2007 Jul;39(1):84-96
references.pmid: 17903700
references.citation: Science. 1994 Jul 29;265(5172):682-4
references.pmid: 8036519
references.citation: J Leukoc Biol. 2004 Jul;76(1):135-44
references.pmid: 15107456
references.citation: J Exp Med. 2011 Oct 24;208(11):2201-7
references.pmid: 21948082
references.citation: CA Cancer J Clin. 2011 Jul-Aug;61(4):250-81
references.pmid: 21617154
references.citation: Science. 1989 Sep 15;245(4923):1238-41
references.pmid: 2551036
references.citation: Nat Rev Immunol. 2010 Dec;10(12):813-25
references.pmid: 21088682
references.citation: J Biol Chem. 1990 May 15;265(14):7760-7
references.pmid: 1692315
references.citation: Am J Physiol Renal Physiol. 2010 Mar;298(3):F779-87
references.pmid: 20042461
references.citation: Cancer Res. 2007 Nov 1;67(21):10501-10
references.pmid: 17974994