Mechanisms underlying the resolution of HDM induced allergic airways disease

Allergic asthma is a chronic inflammatory disease of the lung and deficiencies in pro-resolving mechanisms may contribute to the persistence of inflammation. The overall aim of this project was to establish a resolution model of house dust mite (HDM) induced allergic airway disease (AAD) and identify mediators of resolution. In our model, features of disease, induced by HDM at peak disease 4 hours, airway hyper-reactivity (AHR), Th2 lymphocytes and eosinophils remained significantly elevated 7 days after last challenge, resolving to baseline by 13 days. The levels of FoxP3+ regulatory lymphocytes also follow this pattern. However, as disease waned there was an elevation in the levels of alveolar macrophages and up regulation of the homeostatic molecule CD200R up to 13 days. Exposure to a single i.n administration of HDM in the resolved airways resulted in a rapid increase in Th2 inflammation and AHR suggesting that after resolution of HDM inflammation there is altered immune homeostasis in the lung. The pro-resolving lipid Lipoxin A4 was induced in the lung by HDM exposure and remained detectable during resolution. Depletion of alveolar macrophages during the resolution phase of allergen challenge resulted in delayed clearance of Th2 lymphocytes, airway neutrophils and interstitial macrophages. Conversely, adoptive transfer of alveolar macrophages during resolution resulted in reduced numbers of lung tissue leukocytes, specifically neutrophils and interstitial macrophages. This suggests a cross talk between these macrophage subsets and a novel interaction for pulmonary homeostasis. The anti-inflammatory peptide Annexin A1 is highly expressed by alveolar macrophages and mice deficient in Annexin A1 had enhanced AHR and Th2 immunity response to HDM. Blocking the Annexin A1 receptor FPR2 enhanced AHR and lung inflammation. Conversely, therapeutic administration of an Annexin A1 mimetic improved AHR and Th2 immunity. These studies demonstrate that Annexin A1: FPR2 pathway may be important in HDM disease and that resolution of allergic airways disease is an active process resulting in altered homeostasis of the lung.Open Acces

Abstracts from the NIHR INVOLVE Conference 2017

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Resolution of Allergic Inflammation and Airway Hyperreactivity Is Dependent upon Disruption of the T1/ST2–IL-33 Pathway

Rationale: Although there have been numerous studies on the development of allergen-induced inflammation, the mechanisms leading to resolution of inflammation remain poorly understood. This represents an important consideration because failure to resolve allergen driven inflammation potentially leads to irreversible airway remodeling, characteristic of chronic asthma

Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Rationale: Airway hyperreactivity and remodeling are characteristic features of asthma. Interactions between the airway epithelium and environmental allergens are believed to be important in driving development of pathology, particularly because altered epithelial gene expression is common in individuals with asthma

Lung defense through interleukin-8 carries a cost of chronic lung remodeling and impaired function

RATIONALE: IL-8 dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases including COPD, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible pathologic, changes associated with elevated levels of IL-8 in the lung. OBJECTIVES: To better understand the duality of IL-8 dependent host immunity to bacterial infection and lung pathology, we targeted human IL-8 to express transgenically in murine bronchial epithelium, investigating the impact of over-expression on lung bacterial clearance, host immunity, lung pathology and function. MEASUREMENTS AND MAIN RESULTS: Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation, activation and chemtoaxis. There was enhanced protection from challenge with Pseudomonas aeruginosa and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL2 and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen, OprF, indicating a regulatory T cell phenotype. However, this enhanced bacterial immunity comes at the high price of progressive lung remodelling, with increased inflammation, mucus hyper-secretion, and fibrosis. There is increased expression of Ccl3 and reduced expressioh of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all resulting in impaired lung function with reduced compliance, increased resistance and bronchial hyperreactivity measured by whole body plethysmography. CONCLUSIONS: IL-8 over-expression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodelling and damaged tight junctions, leading to impaired lung function

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of ‘doctor-diagnosed asthma’, thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. Conclusions: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study

Phosphatidylethanolamine-esterified Eicosanoids in the Mouse: TISSUE LOCALIZATION AND INFLAMMATION-DEPENDENT FORMATION IN Th-2 DISEASE

In this study, murine peritoneal macrophages from naïve lavage were found to generate four phospholipids that contain 12-hydroxyeicosatetraenoic acid (12-HETE). They comprise three plasmalogen and one diacyl phosphatidylethanolamines (PEs) (16:0p, 18:1p, 18:0p, and 18:0a at sn-1) and are absent in macrophages from 12/15-lipoxygenase (12/15-LOX)-deficient mice. They are generated acutely in response to calcium mobilization, are primarily cell-associated, and are detected on the outside of the plasma membrane. Levels of 12-HETE-PEs in naïve lavage are in a similar range to those of free 12-HETE (5.5 ± 0.2 ng or 18.5 ± 1.03 ng/lavage for esterified versus free, respectively). In healthy mice, 12/15-LOX-derived 12-HETE-PEs are found in the peritoneal cavity, peritoneal membrane, lymph node, and intestine, with a similar distribution to 12/15-LOX-derived 12-HETE. In vivo generation of 12-HETE-PEs occurs in a Th2-dependent model of murine lung inflammation associated with interleukin-4/interleukin-13 expression. In contrast, in Toll receptor-dependent peritonitis mediated either by live bacteria or bacterial products, 12-HETE-PEs are rapidly cleared during the acute phase then reappear during resolution. The human homolog, 18:0a/15-HETE-PE inhibited human monocyte generation of cytokines in response to lipopolysaccharide. In summary, a new family of lipid mediators generated by murine macrophages during Th2 inflammation are identified and structurally characterized. The studies suggest a new paradigm for lipids generated by 12/15-LOX in inflammation involving formation of esterified eicosanoids