Researchers from the Melbourne University node of the ARC CPTT have published a new paper in interdisciplinary (Cell Press) open access journal iScience titled “A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases“.
Highlights from the paper:
•TGF-β1 extensively impairs GC activity
•Phospho-cofilin1 is a key link of TGF-β1 signalling cascade subserving GC insensitivity
•Phospho-cofilin1-activated phospholipase D (PLD) reduces GC activity
•SMRT induction downstream of PLD mediates TGF-β1 impairment of GC activity
Impaired therapeutic responses to anti-inflammatory glucocorticoids (GC) in chronic respiratory diseases are partly attributable to interleukins and transforming growth factor-β1 (TGF-β1). However, previous efforts to prevent induction of GC insensitivity by targeting established canonical and non-canonical TGF-β1 pathways have been unsuccessful. Here we elucidate a TGF-β1 signalling pathway modulating GC activity that involves in LIM domain kinase 2-mediated phosphorylation of cofilin1. Severe, steroid-resistant asthmatic airway epithelium showed increased levels of immunoreactive phospho-cofilin1. Phospho-cofilin1 was implicated in the activation of phospholipase D (PLD) to generate the effector(s) (lyso)phosphatidic acid, that mimic the TGF-β1-induced GC insensitivity. TGF-β1 induction of the nuclear hormone receptor corepressor, SMRT (NCOR2), was dependent on cofilin1 and PLD activity. Depletion of SMRT prevented GC insensititvity. This pathway for GC insensitivity offers several promising drug targets that potentially enable a safer approach to modulation of TGF-β1 in chronic inflammatory diseases than is afforded by global TGF-β1 inhibition.