The role of Specialized Pro-resolving Mediators in Cystic Fibrosis Airways disease

International audienceCystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients' lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.Genetics of disease, diagnosis and treatmen