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 polleninduced 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 RWPEinduced 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.

Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

“…Lymphocytes, eosinophils, IL-13, and prostaglandins were much greater in the repeatedly exposed mice than in those exposed to mold only once, suggesting a switch from a type 1 immune response to a type 2 immune response. This switch might represent sensitization facilitated by repeated neutrophil influxes to the lungs in response to spores, as has been reported for ragweed (36). Prostaglandin D2, which is elevated in both single-and multiple-dosed mouse lungs, might be involved in recruitment of Th2 cells and eosinophils (37) seen in the multiple-dosed mice, but not the single-dosed mice.…”

Excision release of 5?hydroxycytosine oxidatively induced DNA base lesions from the lung genome by cat dander extract challenge stimulates allergic airway inflammation

“…9,10 In some experiments, WT mice were challenged with five intranasal low doses of CDE (1 μg/60 μL) with or without 5-OH-Cyt on days 0, 1, 2, 3, 4, and, 11 and sacrificed after 72 hours post-challenge (Figure S1C). …”

“…Two investigators who were blinded to the treatment groups assessed mucin production using a minor modification of a method reported 9,10 on a subjective scale of 0, 1, 2, 3, and 4 corresponding to none, mild, moderate, marked, or severe mucin deposition, respectively. The data were expressed as mean of score recorded by two blinded investigators.…”

“…9,10 Repeated challenge with RWPE shifts the immune response to a TLR4-dependent allergic inflammation. 9 Adoptive transfer of purified neutrophils together with RWPE reconstitutes allergic inflammation in Tlr4KO mice. 9 These studies highlight the contribution of innately recruited neutrophils to allergic inflammation.…”

“…9 Adoptive transfer of purified neutrophils together with RWPE reconstitutes allergic inflammation in Tlr4KO mice. 9 These studies highlight the contribution of innately recruited neutrophils to allergic inflammation. Recently, we reported that TLR4 as an innate receptor involved in pollen and cat dander-induced oxidative stress and DNA damage in airways.…”