Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection

Abstract

Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.

An Exploration of the Antioxidative and Anti-Inflammatory Role of Lactiplantibacillus plantarum 106 via Improving Mitochondrial Function

“…Subsequently, bioinformatics analysis was performed on the GSE186886 dataset, identifying 2465 differentially expressed genes (DEGs), including significantly upregulated inflammatory-related genes Csf3, Ccl5, and Ccl. Further KEGG enrichment analysis of the DEGs2 (genes from DEGs1 with |log2 (fold change, FC)| > 2) revealed key inflammatory pathways including cytokine-cytokine receptor interaction, a TNF signaling pathway, and an IL-17 signaling pathway [26]. The GO BP and GO MF analyses additionally indicated enrichment in the innate immune response, inflammatory response, and cytokine activity [27].…”