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Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity.

ABSTRACT: Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils before sensitization abrogated the CHS response. Neutrophil deficiency reduced contact allergen-induced cytokine production, gelatinase release, and reactive oxygen species production in naive mice. Mast cell deficiency inhibited neutrophil accumulation at the site of sensitization. In turn, neutrophils were required for contact allergen-induced release of further neutrophil-attracting chemokines, migration of DCs to the draining lymph nodes, and priming of allergen-specific T cells. Lymph node cells from mice sensitized in the absence of neutrophils failed to transfer sensitization to naive recipients. Furthermore, no CHS response could be induced when neutrophils were depleted before elicitation or when normally sensitized lymph node cells were transferred to neutrophil-deficient recipients, indicating an additional role for neutrophils in the elicitation phase. Collectively, our data identify neutrophils to be critically involved in both the sensitization and elicitation phase of CHS.

SUBMITTER: Weber FC

PROVIDER: S-EPMC4291534 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity.

Weber Felix C FC Németh Tamás T Csepregi Janka Z JZ Dudeck Anne A Roers Axel A Ozsvári Béla B Oswald Eva E Puskás László G LG Jakob Thilo T Mócsai Attila A Martin Stefan F SF

The Journal of experimental medicine 20141215 1

Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils ...[more]

PMID: 25512469

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Project description:ObjectivesExperiments using P2X3 knock-out mice or more general P2X receptor antagonists suggest that P2X3 receptors contribute to visceral hypersensitivity. We aimed to investigate the effect of the selective P2X3 antagonist A-317491 on visceral sensitivity under physiological conditions, during acute colitis and in the post-inflammatory phase of colitis.MethodsTrinitrobenzene sulphonic-acid colitis was monitored by colonoscopy: on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Visceral sensitivity was assessed by quantifying visceromotor responses to colorectal distension in controls, rats with acute colitis and post-colitis rats. A-317491 was administered 30 min prior to visceral sensitivity testing. Expression of P2X3 receptors (RT-PCR and immunohistochemistry) and the intracellular signalling molecules cdk5, csk and CASK (RT-PCR) were quantified in colonic tissue and dorsal root ganglia. ATP release in response to colorectal distension was measured by luminiscence.ResultsRats with acute TNBS-colitis displayed significant visceral hypersensitivity that was dose-dependently, but not fully, reversed by A-317491. Hypersenstivity was accompanied by an increased colonic release of ATP. Post-colitis rats also displayed visceral hypersensitivity that was dose-dependently reduced and fully normalized by A-317491 without increased release of ATP. A-317491 did not modify visceral sensitivity in controls. P2X3 mRNA and protein expression in the colon and dorsal root ganglia were similar in control, acute colitis and post-colitis groups, while colonic mRNA expression of cdk5, csk and CASK was increased in the post-colitis group only.ConclusionsThese findings indicate that P2X3 receptors are not involved in sensory signaling under physiological conditions whereas they modulate visceral hypersensitivity during acute TNBS-colitis and even more so in the post-inflammatory phase, albeit via different mechanisms of sensitization, validating P2X3 receptors as potential new targets in the treatment of abdominal pain syndromes.

Project description:Genes involved in the inflammatory response resulting in allergic contact dermatitis (ACD) are only partly known. In this study, we introduce the use of high density oligonucleotide arrays for gene expression profiling in human skin during the elicitation of ACD. Skin biopsies from normal and nickel-exposed skin were obtained from 7 nickel-allergic patients and 5 non-allergic controls at four different time points during elicitation of eczema: 0h, 7h, 48h and 96h. Each gene expression profile was analysed by hybridization to high density oligonucletide arrays. Cluster analysis of 74 genes found to be differentially expressed in the patients over time revealed that the patient samples may be categorised into two groups: An early time point group (0h and 7h) and a late time point group (48h and 96h). Compared to the early time points, late time point skin samples were characterised by the up-regulation of inflammatory molecules including genes involved in the class I antigen presenting pathway and genes involved in lymphocyte adhesion and motility ; Correspondence analysis including both patients and controls revealed three distinct groups: i) the control group, ii) the early time point patient group (0h and 7h) and iii) the late time point patient group (48h and 96h). Experiment Overall Design: For the microarray study, 7 nickel-allergic patients and 5 non-allergic controls were recruited. All subjects were female. The skin covering the upper nates was exposed to nickel delivered during a patch test. Skin biopsies were taken to generate a time-series. Skin was exposed to nickel for 0h, 7h, 48h and 96h. Experiment Overall Design: All nickel allergic patients reacted with visible eczama at the 48h and 96h time-points. No eczema was vissible at the 0h or 7h time-points. Control subjects did not show visible eczema at any time-point. Experiment Overall Design: RNA was extracted from the skin biopsies and 34 biopsies yielded RNA of sufficient quantity and quality for micro-array analysis.

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Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity.

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Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity.

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