MAP3K8 Regulates Cox-2–Mediated Prostaglandin E2 Production in the Lung and Suppresses Pulmonary Inflammation and Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by exuberant deposition of extracellular matrix components, leading to the deterioration of lung architecture and respiratory functions. Profibrotic mechanisms are controlled by multiple regulatory molecules, including MAPKs, in turn regulated by multiple phosphorylation cascades. MAP3K8 is an MAPK kinase kinase suggested to pleiotropically regulate multiple pathogenic pathways in the context of inflammation and cancer; however, a possible role in the pathogenesis of IPF has not been investigated. In this report, MAP3K8 mRNA levels were found decreased in the lungs of IPF patients and of mice upon bleomycin-induced pulmonary fibrosis. Ubiquitous genetic deletion of Map3k8 in mice exacerbated the modeled disease, whereas bone marrow transfer experiments indicated that although MAP3K8 regulatory functions are active in both hematopoietic and nonhematopoietic cells, Map3k8 in hematopoietic cells has a more dominant role. Macrophagespecific deletion of Map3k8 was further found to be sufficient for disease exacerbation thus confirming a major role for macrophages in pulmonary fibrotic responses and suggesting a main role for Map3k8 in the homeostasis of their effector functions in the lung. Map3k8 deficiency was further shown to be associated with decreased Cox-2 expression, followed by a decrease in PGE 2 production in the lung; accordingly, exogenous administration of PGE 2 reduced inflammation and reversed the exacerbated fibrotic profile of Map3k8 2/2 mice. Therefore, MAP3K8 has a central role in the regulation of inflammatory responses and Cox-2-mediated PGE 2 production in the lung, and the attenuation of its expression is integral to pulmonary fibrosis development.

Fibromine is a multi-omics database and mining tool for target discovery in pulmonary fibrosis

“…In addition, inspecting MAP3K8 in higher resolution data via the explorer’s Map to single cell data feature instantly revealed an “enrichment” of gene’s expression in monocytic-lineage cells. These findings were further validated in the bleomycin-induced animal model of pulmonary fibrosis, where genetic deletion of MAP3K8 was shown to exacerbate the modeled disease 30 . All results impelling us to wet lab examination of MAP3K8 expression during lung fibrosis can be replicated using the Example button of Gene explorer and then filtering the DEG statistics table for lung tissue and IPF_vs_Ctrl comparisons (Supplementary Fig.…”

“…Fibromine’s Gene explorer enables interrogation of single/multiple gene expression motifs (consistently recurring DEA results across same/similar experimental conditions), a very useful feature to validate wet laboratory findings and quickly deepen novel hypotheses formation. For example, following leads from cancer and inflammatory diseases, our laboratory has used a primary version of Fibromine’s Gene explorer to discover that based on the three larger IPF_vs_Ctrl bulk lung datasets, MAP3K8 is down-regulated in IPF patients’ lungs 30 . In addition, inspecting MAP3K8 in higher resolution data via the explorer’s Map to single cell data feature instantly revealed an “enrichment” of gene’s expression in monocytic-lineage cells.…”

Influenza-induced Tpl2 expression within alveolar epithelial cells is dispensable for host viral control and anti-viral immunity

“…Multiple lines of evidence have recently implicated Tpl2 in restraining fibrotic responses, both in intestinal myofibroblast-mediated fibrosis in the gut [ 23 ] and in bleomycin-induce lung fibrosis [ 22 ]. Because pulmonary fibrosis can impair lung function during influenza infection [ 40 ], we assessed whether Tpl2 protects against influenza-induced lung injury by inhibiting pulmonary fibrosis.…”

“…Given the cell-type and stimulus-specific nature of Tpl2 [ 9 ], other radioresistant cell types, such as stromal cell populations, including endothelial cells and myofibroblasts also need to be considered. Previous studies have shown important roles for Tpl2 in intestinal [ 23 ] and lung myofibroblast [ 22 ] and lung endothelial cells [ 50 ]. However, whether and how Tpl2 functions in these cell types to induce protective antiviral responses is currently unknown.…”

“…demonstrated that Tpl2 -/- mice have enhanced susceptibility to a low pathogenic strain of influenza A (x31; H3N2), and the increased susceptibility was caused by Tpl2 deficiency within radioresistant cells [ 18 ]. Multiple lines of evidence now support that Tpl2 plays critical regulatory roles within radioresistant non-hematopoietic cells [ 22 , 23 ]. For instance, Tpl2 signaling within intestinal subepithelial myofibroblasts modulates hepatocyte growth factor and epithelial cell proliferation during colitis-induced colorectal carcinogenesis [ 23 ].…”