title: Neutrophils Self-Regulate Immune Complex-Mediated Cutaneous Inflammation through CXCL2.
abstract: Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is especially associated with vasculitis of the skin, but the mechanisms that regulate this type III hypersensitivity process remain poorly understood. Here, using a combination of multiphoton intravital microscopy and genomic approaches, we re-examined the cutaneous reverse passive Arthus reaction and observed that IC-activated neutrophils underwent transmigration, triggered further IC formation, and transported these ICs into the interstitium, whereas neutrophil depletion drastically reduced IC formation and ameliorated vascular leakage in vivo. Thereafter, we show that these neutrophils expressed high levels of CXCL2, which further amplified neutrophil recruitment and activation in an autocrine and/or paracrine manner. Notably, CXCL1 expression was restricted to tissue-resident cell types, but IC-activated neutrophils may also indirectly, via soluble factors, modulate macrophage CXCL1 expression. Consistent with their distinct cellular origins and localization, only neutralization of CXCL2 but not CXCL1 in the interstitium effectively reduced neutrophil recruitment. In summary, our study establishes that neutrophils are able to self-regulate their own recruitment and responses during IC-mediated inflammation through a CXCL2-driven feed forward loop.
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Jackson LiangYao
authors.initials: JL
authors.lastname: Li
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Chun Hwee
authors.initials: CH
authors.lastname: Lim
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Fen Wei
authors.initials: FW
authors.lastname: Tay
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Goh
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Sapna
authors.initials: S
authors.lastname: Devi
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore; Department of Microbiology, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Benoit
authors.initials: B
authors.lastname: Malleret
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Bernett
authors.initials: B
authors.lastname: Lee
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Nadja
authors.initials: N
authors.lastname: Bakocevic
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Shu Zhen
authors.initials: SZ
authors.lastname: Chong
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Evrard
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tanizaki
authors.affiliation: Department of Microbiology, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Hwee Ying
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Department of Microbiology, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zolezzi
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Department of Microbiology, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Veronique
authors.initials: V
authors.lastname: Angeli
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: St John
authors.affiliation: Division of Dermatology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Harris
authors.affiliation: Medical Department, National Skin Centre, Singapore.
authors.forename: Hong Liang
authors.initials: HL
authors.lastname: Tey
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Suet Mien
authors.initials: SM
authors.lastname: Tan
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Centenary Institute for Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia; Discipline of Dermatology, University of Sydney, Sydney, New South Wales, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore. Electronic address: Ng_Lai_Guan@immunol.a-star.edu.sg.
authors.forename: Lai Guan
authors.initials: LG
authors.lastname: Ng
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000276:immunology / Q000378:metabolism*; D003872:Dermatitis / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007105:Immune Complex Diseases / Q000276:immunology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D000936:Antigen-Antibody Complex; C499706:CXCL2 protein, human; D054426:Chemokine CXCL2; D018836:Inflammation Mediators; D012333:RNA, Messenger