Targeting periostin reduces inflammation and respiratory barrier injury in lung diseases.

This is the final version of the article, which has been published in final form at: https://www.lestudium-ias.com/content/targeting-periostin-reduces-inflammation-and-respiratory-barrier-injury-lung-diseasesInternational audiencePeriostin (POSTN) is a matricellular protein that plays a key role in development and repair within the biological matrix of the lung. POSTN is highly expressed in several cell types in lung such as epithelial or endothelial cells, fibroblasts, smooth muscle and mast cells, contributing to mucus secretion, alveolar epithelial repair, and lung fibrosis. However, the underlying mechanism how POSTN contributes to the development of lung inflammation remains unclear. In the current study, we attempted to determine whether treatment with a monoclonal anti-POSTN antibody induces a significant inhibition of asthmatic reactions in a mouse asthma model. Mice sensitized and challenged with papain evidenced an increased periostin expression in lung and typical asthmatic reactions, as follows: an increase in the number of eosinophils in bronchoalveolar lavage fluid; a marked influx of inflammatory cells into the lung around blood vessels and airways, and Th2 cytokines including IL-4 and IL-5 and chemokines in the bronchoalveolar lavage (BAL) fluid; emphysema; the detection of thymic stromal lymphopoietin (TSLP) produced by epithelial cells. However, the administration of anti-POSTN prior to the final airway papain challenge resulted in a significant inhibition of all asthmatic reactions. We also demonstrated that anti-POSTN antibody treatment resulted in significant reductions on collagen expression and a reduction in the increased eosinophil. The treatment of animals with anti-POSTN resulted in a significant reduction in the concentrations of the chemokines (CCL-11 and CCL-17) in the airways, without any concomitant increase in the concentration of Th1 cytokines. This study identifies a novel therapeutic strategy for airway hyperresponsiveness, which uses antibodies reactive against POSTN via the inhibition of the Th2 response. It also provides theoretical evidence for the control of allergic asthma and fibrosis by targeting POSTN

Inflammasome, IL-1 and inflammation in ozone-induced lung injury.

Exposure to ambient ozone causes airway hyperreactivity and lung inflammation, which represent an important health concern in humans. Recent clinical and experimental studies contributed to the understanding of the mechanisms of epithelial injury, inflammation and airway hyperreactivity, which is reviewed here. The present data suggest that ozone induced oxidative stress causes inflammasome activation with the release of IL-1, other cytokines and proteases driving lung inflammation leading to the destruction of alveolar epithelia with emphysema and respiratory failure. Insights in the pathogenic pathway may allow to identify novel biomarkers of ozone-induced lung disease and therapeutic targets

G-quadruplex DNA targeting alters class-switch recombination in B cells and attenuates allergic inflammation

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NLRP6 negatively regulates type 2 immune responses in mice

International audienceBackground: Inflammasomes are large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection. Following activation, inflammasomes trigger cell death and the release of biologically active forms of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome is required for IL-18 secretion by intestinal epithelial cells, macrophages, and T cells, contributing to homeostasis and self-defense against pathogenic microbes. However, the involvement of NLRP6 in type 2 lung inflammation remains elusive.Methods: Wild-type (WT) and Nlrp6−/− mice were used. Birch pollen extract (BPE)-induced allergic lung inflammation, eosinophil recruitment, Th2-related cytokine and chemokine production, airway hyperresponsiveness, and lung histopathology, Th2 cell differentiation, GATA3, and Th2 cytokines expression, were determined. Nippostrongylus brasiliensis (Nb) infection, worm count in intestine, type 2 innate lymphoid cell (ILC2), and Th2 cells in lungs were evaluated.Results: We demonstrate in Nlrp6−/− mice that a mixed Th2/Th17 immune responses prevailed following birch pollen challenge with increased eosinophils, ILC2, Th2, and Th17 cell induction and reduced IL-18 production. Nippostrongylus brasiliensis infected Nlrp6−/− mice featured enhanced early expulsion of the parasite due to enhanced type 2 immune responses compared to WT hosts. In vitro, NLRP6 repressed Th2 polarization, as shown by increased Th2 cytokines and higher expression of the transcription factor GATA3 in the absence of NLRP6. Exogenous IL-18 administration partially reduced the enhanced airways inflammation in Nlrp6−/− mice.Conclusions: In summary, our data identify NLRP6 as a negative regulator of type 2 immune responses

Bromodomain and extraterminal (BET) protein inhibition of IgG/IgE production in murine B cells is counter-balanced by a strong Th2 bias

International audienceOBJECTIVES: Inhibitors of bromodomain and extra terminal domain (BET) proteins are a new and growing class of anti-cancer drugs, which decrease oncogene expression by targeting superenhancers. Antibody production is another physiological process relying on superenhancers, and it remains to be clarified whether potential immunomodulatory properties of BET inhibitors might impact humoral immunity and allergy.METHODS: We thus evaluated humoral immune responses and their Th2 context in vitro and in vivo in mice following treatment with the classical BET-inhibitor JQ1. We quantified immunoglobulin (Ig) and antibody production by B cells either stimulated in vitro or obtained from immunised mice. JQ1 effects on class switching and activation-induced deaminase loading were determined, together with modifications of B, T follicular helper (Tfh) and T helper 2 (Th2) populations. JQ1 was finally tested in B-cell-dependent models of immune disorders.RESULTS: Bromodomain and extra terminal domain inhibition reduced class switching, Ig expression on B cells and antibody secretion and was correlated with decreased numbers of Tfh cells. However, JQ1 strongly increased the proportion of GATA3(+) Th2 cells and the secretion of corresponding cytokines. In a mouse allergic model of lung inflammation, JQ1 did not affect eosinophil infiltration or mucus production but enhanced Th2 cytokine production and aggravated clinical manifestations.CONCLUSION: Altogether, BET inhibition thus interweaves intrinsic negative effects on B cells with a parallel complex reshaping of T-cell polarisation which can increase type 2 cytokines and eventually promote B-cell-dependent immunopathology. These opposite and potentially hazardous immunomodulatory effects raise concerns for clinical use of BET inhibitors in patients with immune disorders

Protein kinase C θ controls type 2 innate lymphoid cell and TH2 responses to house dust mite allergen.

IF 13.081International audienceBACKGROUND:Protein kinase C (PKC) θ, a serine/threonine kinase, is involved in TH2 cell activation and proliferation. Type 2 innate lymphoid cells (ILC2s) resemble TH2 cells and produce the TH2 cytokines IL-5 and IL-13 but lack antigen-specific receptors. The mechanism by which PKC-θ drives innate immune cells to instruct TH2 responses in patients with allergic lung inflammation remains unknown.OBJECTIVES:We hypothesized that PKC-θ contributes to ILC2 activation and might be necessary for ILC2s to instruct the TH2 response.METHODS:PRKCQ gene expression was assessed in innate lymphoid cell subsets purified from human PBMCs and mouse lung ILC2s. ILC2 activation and eosinophil recruitment, TH2-related cytokine and chemokine production, lung histopathology, interferon regulatory factor 4 (IRF4) mRNA expression, and nuclear factor of activated T cells (NFAT1) protein expression were determined. Adoptive transfer of ILC2s from wild-type mice was performed in wild-type and PKC-θ-deficient (PKC-θ-/-) mice.RESULTS:Here we report that PKC-θ is expressed in both human and mouse ILC2s. Mice lacking PKC-θ had reduced ILC2 numbers, TH2 cell numbers and activation, airway hyperresponsiveness, and expression of the transcription factors IRF4 and NFAT1. Importantly, adoptive transfer of ILC2s restored eosinophil influx and IL-4, IL-5 and IL-13 production in lung tissue, as well as TH2 cell activation. The pharmacologic PKC-θ inhibitor (Compound 20) administered during allergen challenge reduced ILC2 numbers and activation, as well as airway inflammation and IRF4 and NFAT1 expression.CONCLUSIONS:Therefore our findings identify PKC-θ as a critical factor for ILC2 activation that contributes to TH2 cell differentiation, which is associated with IRF4 and NFAT1 expression in allergic lung inflammation

IL-1R1-MyD88 axis elicits papain-induced lung inflammation

Allergic asthma is characterized by a strong Th2 response with inflammatory cell recruitment and structural changes in the lung. Papain is a protease allergen disrupting the airway epithelium triggering a rapid inflammation with eosinophilia mediated by innate lymphoid cell activation (ILC2) and leading to a Th2 immune response. In this study, we focused on inflammatory responses to a single exposure to papain and showed that intranasal administration of papain results in the recruitment of inflammatory cells, including neutrophils and eosinophils with a rapid production of IL-1α, IL-1β, and IL-33. The inflammatory response is abrogated in the absence of IL-1R1 and MyD88. To decipher the cell type(s) involved in MyD88-dependent IL-1R1/MyD88 signaling, we used new cell-specific MyD88-deficient mice and found that the deletion of MyD88 signaling in single cell types such as T cells, epithelial cells, CD11c-positive or myeloid cells leads to only a partial inhibition compared to complete absence of MyD88, suggesting that several cell types contribute to the response. Importantly, the inflammatory response is largely ST2 and IL-36R independent. In conclusion, IL-1R1 signaling via MyD88 is critical for the first step of inflammatory response to papain