Prostaglandin E₂ attenuates lung fibroblast differentiation via inactivation of yes‐associated protein signaling

Abstract

Prostaglandin E2 (PGE2) has been implicated in counteracting fibroblast differentiation by TGFβ1 during pulmonary fibrosis. However, the precise mechanism is not well understood. We show here that PGE2 via EP2R and EP4R inhibits the expression of mechanosensory molecules Lysyl Oxidase Like 2 (LOXL2), myocardin‐related transcription factor A (MRTF‐A), ECM proteins, plasminogen activation inhibitor 1 (PAI‐1), fibronectin (FN), α‐smooth muscle actin (α‐SMA), and redox sensor (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)) required for TGFβ1‐mediated fibroblast differentiation. We further demonstrate that PGE2 inhibits fibrotic signaling via Yes‐associated protein (YAP) but does so independently from its actions on SMAD phosphorylation and conserved cylindromatosis (CYLD; deubiquitinase) expression. Mechanistically, PGE2 phosphorylates/inactivates YAP downstream of EP2R/Gαs and restrains its translocation to the nucleus, thus inhibiting its interaction with TEA domain family members (TEADs) and transcription of fibrotic genes. Importantly, pharmacological or siRNA‐mediated inhibition of YAP significantly downregulates TGFβ1‐mediated fibrotic gene expression and myofibroblast formation. Notably, YAP expression is upregulated in the lungs of D. farinae‐treated wild type (WT) mice relative to saline‐treated WT mice. Our results unravel a unique role for PGE2‐YAP interactions in fibroblast differentiation, and that PGE2/YAP inhibition can be used as a novel therapeutic target in the treatment of pathological conditions associated with myofibroblasts like asthma.