CXCR2 Is Required for Neutrophilic Airway Inflammation and Hyperresponsiveness in a Mouse Model of Human Rhinovirus Infection

Abstract

Human rhinovirus (RV) infection is responsible for the majority of virus-induced asthma exacerbations. Using a mouse model of human RV infection, we sought to determine the requirement of CXCR2, the receptor for ELR-positive CXC chemokines, for RV-induced airway neutrophilia and hyperresponsiveness. Wild-type and CXCR2−/− mice were inoculated intranasally with RV1B or sham HeLa cell supernatant. Following RV1B infection, CXCR2−/− mice showed reduced airway and lung neutrophils and cholinergic responsiveness compared with wild-type mice. Similar results were obtained in mice treated with neutralizing Ab to Ly6G, a neutrophil-depleting Ab. Lungs from RV-infected, CXCR2−/− mice showed significantly reduced production of TNF-α, MIP-2/CXCL2, and KC/CXCL1 and lower expression of MUC5B compared with RV-treated wild-type mice. The requirement of TNF-α for RV1B-induced airway responses was tested using TNFR1−/− mice. TNFR1−/− animals displayed reduced airway responsiveness to RV1B, even when exogenous MIP-2 was added to the airways. We conclude that CXCR2 is required for RV-induced neutrophilic airway inflammation and that neutrophil TNF-α release is required for airway hyperresponsiveness.

Cxcl8 (IL-8) Mediates Neutrophil Recruitment and Behavior in the Zebrafish Inflammatory Response

“…Our analysis revealed that both chemokines are necessary for a normal neutrophil response, as in their absence, neutrophil recruitment to the wound was severely impaired. These findings are in agreement with the reduced neutrophil recruitment observed in inflammation in knockout mice for CXCR1, CXCR2, or CXCL1 (one of the mouse CXCL8 functional homologs) (40)(41)(42)(43)(44). Furthermore the mRNA levels of key proinflammatory mediators, such as IL-1b and PTGS2b, were affected in both morphants, strongly suggesting that in the absence of either Cxcl8, zebrafish acute inflammation is significantly attenuated.…”

Coordinate activation of inflammatory gene networks, alveolar destruction and neonatal death in AKNA deficient mice

“…These data additionally emphasize the relevance of mechanisms that may be involved in the initiation and progression of complex pathologies such as anaphylaxis and tumorigenesis [23,56,57,59]. Although our studies are by no means exhaustive, the combined data from AKNA KO and KO2 mice concur with our hypothesis that AKNA has a regulatory function on gene transcription networks, which we suggest is linked to the mechanisms that control the degree of neutrophil responses to pathogen invasion ( Figure 8D).…”

“…Hence, in the context of a linkage with strain in mice and potentially with race in humans, we consider two hypothetical scenarios in AKNA deficiency: (1) acute and fatal hyper-reactions in genetically prone populations [56,57] and (2) subtle states of inflammation in populations with no inherent genetic susceptibility that create a microenvironment that facilitates the initiation and progression of degenerative and/or neoplastic disorders [58].…”

Neonatal Hyperoxia Contributes Additively to Cigarette Smoke–Induced Chronic Obstructive Pulmonary Disease Changes in Adult Mice

“…In the CS-only and O 2 1CS mice, we found increased numbers of inflammatory cells in the BALF and increased expression of CXCR2/IL8Ra lung mRNA, suggesting a correlation between chronic CS exposure and increased lung inflammation. Induction of CXCR2/IL8Ra has previously been demonstrated in animal models of CSinduced COPD, Streptococcus pneumoniae, and rhinovirusinduced airway inflammation (30)(31)(32)(33). We did not find an association between early postnatal hyperoxia exposure and increased inflammation in the adult lung.…”