The proinflammatory cytokine IL-36γ is a global discriminator of harmless microbes and invasive pathogens within epithelial tissues

Epithelial tissues represent vital interfaces between organisms and their environment. As they are constantly exposed to harmful pathogens, innocuous commensals, and environmental microbes, it is essential they sense and elicit appropriate responses toward these different types of microbes. Here, we demonstrate that the epithelial cytokine interleukin-36γ (IL-36γ) acts as a global discriminator of pathogenic and harmless microbes via cell damage and proteolytic activation. We show that intracellular pro-IL-36γ is upregulated by both fungal and bacterial epithelial microbes; yet, it is only liberated from cells, and subsequently processed to its mature, potent, proinflammatory form, by pathogen-mediated cell damage and pathogen-derived proteases. This work demonstrates that IL-36γ senses pathogen-induced cell damage and proteolytic activity and is a key initiator of immune responses and pathological inflammation within epithelial tissues. As an apically located epithelial proinflammatory cytokine, we therefore propose that IL-36γ is critical as the initial discriminator of harmless microbes and invasive pathogens within epithelial tissues

Expression of Actin-interacting Protein 1 Suppresses Impaired Chemotaxis of Dictyostelium Cells Lacking the Na+-H+ Exchanger NHE1

Dictyostelium cells lacking the intracellular pH regulator NHE1 have defective chemotaxis. A modifier screen and reconstitution studies show expression of recombinant actin interacting protein 1 (Aip1) suppresses the Ddnhe1-phenotype. Aip1 promotes cofilin-dependent actin remodeling, which is likely a major determinant in pH-dependent chemotaxis

Clinically validated markers of the extracellular matrix remodelling are altered by potential anti-fibrotic compounds in a human lung fibrosis ex vivo model

Background: Pulmonary fibrosis (PF) is characterized by excessive extracellular matrix (ECM) remodeling. Clinically validated ECM neoepitopes markers, related to progressive PF, may be useful for the evaluation of potential anti-fibrotic effects. Aim: The aim was to evaluate ECM remodelling (ECMR) in a human ex vivo precision-cut lung slice (PCLS) model. Methods: Human PF tissue was collected from two donors during lung transplantation. Within 24hours, the lungs were processed into PCLSs. The slices were cultured 2 pr/well and in triplicates for 48hours in serum free medium with 1nM-10μM nintedanib or 100pM-1µM mTOR/PI3K inhibitor omipalisib (GSK2126458). Responsiveness was tested using Lipopolysaccaride (LPS) and cytotoxicity using lactate dehydrogenase (LDH). Markers of collagen type I, III and VI formation (P1NP, PRO-C3, PRO-C6) and type III collagen degradation (C3M) were assessed in the supernatants. The subpleural and central lung regions were used and evaluated by hematoxylin and eosin staining. Results: The tissue from both donors was responsive to LPS and no toxicity was seen with the selected compound doses using LDH. P1NP, PRO-C3, and C3M were significantly reduced by 1nM-1µM omipalisib (p<0.05-0.001) including the IC50 value around 40-50nM. Non-significant reductions of PRO-C6 were seen. Data varied depending on region and donor. Similar trends were observed for nintedanib, however no significant changes were seen in this model. Conclusion: We found that an mTOR/PI3K inhibitor decreased markers of ECMR in a human PF ex vivo model, potential as a tool for evaluating anti-fibrotic compounds in a 3D PF structure