title: Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment.
abstract: Neutrophil recruitment is a hallmark of rapid innate immune responses. Exposure of airways of naive mice to pollens rapidly induces neutrophil recruitment. The innate mechanisms that regulate pollen-induced neutrophil recruitment and the contribution of this neutrophilic response to subsequent induction of allergic sensitization and inflammation need to be elucidated. Here we show that ragweed pollen extract (RWPE) challenge in naive mice induces C-X-C motif ligand (CXCL) chemokine synthesis, which stimulates chemokine (C-X-C motif) receptor 2 (CXCR2)-dependent recruitment of neutrophils into the airways. Deletion of Toll-like receptor 4 (TLR4) abolishes CXCL chemokine secretion and neutrophil recruitment induced by a single RWPE challenge and inhibits induction of allergic sensitization and airway inflammation after repeated exposures to RWPE. Forced induction of CXCL chemokine secretion and neutrophil recruitment in mice lacking TLR4 also reconstitutes the ability of multiple challenges of RWPE to induce allergic airway inflammation. Blocking RWPE-induced neutrophil recruitment in wild-type mice by administration of a CXCR2 inhibitor inhibits the ability of repeated exposures to RWPE to stimulate allergic sensitization and airway inflammation. Administration of neutrophils derived from naive donor mice into the airways of Tlr4 knockout recipient mice after each repeated RWPE challenge reconstitutes allergic sensitization and inflammation in these mice. Together these observations indicate that pollen-induced recruitment of neutrophils is TLR4 and CXCR2 dependent and that recruitment of neutrophils is a critical rate-limiting event that stimulates induction of allergic sensitization and airway inflammation. Inhibiting pollen-induced recruitment of neutrophils, such as by administration of CXCR2 antagonists, may be a novel strategy to prevent initiation of pollen-induced allergic airway inflammation.
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology.
authors.forename: Koa
authors.initials: K
authors.lastname: Hosoki
authors.affiliation: 2 Department of Microbiology and Immunology.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Aguilera-Aguirre
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology.|3 Sealy Center for Molecular Medicine, and.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: 3 Sealy Center for Molecular Medicine, and.|4 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurosky
authors.affiliation: 2 Department of Microbiology and Immunology.|3 Sealy Center for Molecular Medicine, and.
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology.|3 Sealy Center for Molecular Medicine, and.
authors.forename: Sanjiv
authors.identifier: http://orcid.org/0000-0002-7267-0025
authors.initials: S
authors.lastname: Sur
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D052179:Antigens, Plant / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010936:Plant Extracts / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics
chemical_list: D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D052179:Antigens, Plant; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D023063:Receptors, Interleukin-8B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C433085:ragweed pollen
keywords: CXCR2; Toll-like receptor 4; allergic inflammation; neutrophil; reactive oxygen species