Emerging roles of the Hippo signaling pathway in modulating immune response and inflammation‐driven tissue repair and remodeling

Abstract

Inflammation is an evolutionarily conserved process and part of the body's defense mechanism. Inflammation leads to the activation of immune and non-immune cells that protect the host tissue/organs from injury or intruding pathogens. The Hippo pathway is an evolutionarily conserved kinase cascade with an established role in regulating cell proliferation, survival, and differentiation. It is involved in diverse biological processes, including organ size control and tissue homeostasis. Recent clinical and pre-clinical studies have shown that the Hippo signaling pathway is also associated with injury-and pathogen-induced tissue inflammation and associated immunopathology. In this review, we have summarized the recent findings related to the involvement of the Hippo signaling pathway in modulating the immune response in different acute and chronic inflammatory diseases and its impact on tissue repair and remodeling.

New Insights into Hippo/YAP Signaling in Fibrotic Diseases

“…Furthermore, activated YAP/TAZ in interstitial myofibroblasts promotes kidney fibrosis [16], while hyperactivated YAP/TAZ in nonfibroblast cells, such as macrophages [29,30], epithelial cells [31][32][33], and hepatocytes [8,10] contribute to the pathogenesis of fibrosis. Consistent with these findings showing the fibrotic effects of YAP/TAZ, their inactivation was found to be beneficial for preventing myofibroblast formation and fibrosis development [34]. Like YAP/TAZ, Hippo kinases are also known to contribute to a range of fibrotic diseases [20,[35][36][37][38].…”

Alteration in branching morphogenesis via YAP/TAZ in fibroblasts of fetal lungs in an LPS-induced inflammation model

“…It was found to promote branching morphogenesis by regulating not merely the balance between distal epithelium differentiation and proliferation but the ECM as well (Rockich et al 2013 ). As a consequence, decreasing expressions of FGF10, SOX2 and SOX9 by fibroblasts with LPS treatment could be associated with branching defects under inflammation (Mia and Singh 2022 ).…”

“…Consistently, the downregulation of tissue homeostasis and remodelling by LPS were observed. Hippo signaling pathway was previously reported to be involved in tissue homeostasis and remodeling, with delayed cell proliferation, epithelial regeneration and lung injury recovery from LPS by YAP inhibitor (Liu et al 2020 ; Mia and Singh 2022 ). The impaired regeneration of alveolar epithelial due to lack of YAP/TAZ was accompanied with failure in terminating NF-κB proinflammatory signal pathway (LaCanna et al 2019 ).…”

Infection and immunity: ‘There Are Things Out There You (Don't) Need To Know About’

“…Despite different activating stimuli and divergent immune responses, cells exploit rather common mechanisms to ensure efficient signal transduction between the detection of inflammatory stimuli (be that pathogen‐associated molecular patterns or messenger molecules from other cells) by cell receptors and the activation of the appropriate molecular response. Mia and Singh [12] discuss how an evolutionary conserved Hippo pathway regulates the proliferation and differentiation of macrophages and epithelial cells in the diverse settings of cardiovascular, pulmonary, liver and gut inflammation, and neuroinflammation. One of the key events in numerous intracellular signalling pathways is the formation of the aggregate‐like macromolecular signalling hub often nucleated by the members of the death domain fold (DDF) superfamily of proteins, extensively reviewed by Huoh and Hur [13].…”