title: Type 2 Interleukin-4 Receptor Signaling in Neutrophils Antagonizes Their Expansion and Migration during Infection and Inflammation.
abstract: Neutrophils are the first immune cells recruited to sites of inflammation and infection. However, patients with allergic disorders such as atopic dermatitis show a paucity of skin neutrophils and are prone to bacterial skin infections, suggesting that allergic inflammation curtails neutrophil responses. Here we have shown that the type 2 cell signature cytokine interleukin-4 (IL-4) hampers neutrophil expansion and migration by antagonizing granulocyte colony-stimulating factor (G-CSF) and chemokine receptor-mediated signals. Cutaneous bacterial infection in mice was exacerbated by IL-4 signaling and improved with IL-4 inhibition, each outcome inversely correlating with neutrophil migration to skin. Likewise, systemic bacterial infection was worsened by heightened IL-4 activity, with IL-4 restricting G-CSF-induced neutrophil expansion and migration to tissues by affecting CXCR2-CXCR4 chemokine signaling in neutrophils. These effects were dependent on IL-4 acting through type 2 IL-4 receptors on neutrophils. Thus, targeting IL-4 might be beneficial in neutropenic conditions with increased susceptibility to bacterial infections.
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Woytschak
authors.affiliation: Department of Infectious Diseases, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Nadia
authors.initials: N
authors.lastname: Keller
authors.affiliation: Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Krieg
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzieri
authors.affiliation: Immunopathogenesis Section, Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD 20892-0425, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Thompson
authors.affiliation: Immunopathogenesis Section, Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD 20892-0425, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.affiliation: Department of Infectious Diseases, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Annelies S
authors.initials: AS
authors.lastname: Zinkernagel
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland. Electronic address: onur.boyman@uzh.ch.
authors.forename: Onur
authors.initials: O
authors.lastname: Boyman
mesh_terms: D000818:Animals; D058491:Bacterial Load; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology*; D008089:Listeria monocytogenes / Q000502:physiology*; D008088:Listeriosis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit