Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Abstract

While our previous studies suggest that limiting bleomycin-induced complement activation suppresses TGF-β signaling, the specific hierarchical interactions between TGF-β and complement in lung fibrosis are unclear. Herein, we investigated the mechanisms underlying TGF-β-induced complement activation in the pathogenesis of lung fibrosis. C57-BL6 mice were given intratracheal instillations of adenoviral vectors overexpressing TGF-β (Ad-TGFβ) or the firefly gene-luciferase (Ad-Luc; control). Two weeks later, mice with fibrotic lungs were instilled RNAi specific to receptors for C3a or C5a-C3ar or C5ar, and sacrificed at day 28. Histopathological analyses revealed that genetic silencing of C3ar or C5ar arrested the progression of TGF-β-induced lung fibrosis, collagen deposition and content (hydroxyproline, col1a1/2); and significantly suppressed local complement activation. With genetic silencing of either C3ar or C5ar, in Ad-TGFβ-injured lungs: we detected the recovery of Smad7 (TGF-β inhibitor) and diminished local release of DAF (membrane-bound complement inhibitor); in vitro: TGF-β-mediated loss of DAF was prevented. Conversely, blockade of the TGF-β receptor prevented C3a-mediated loss of DAF in both normal primary human alveolar and small airway epithelial cells. Of the 52 miRNAs analyzed as part of the Affymetrix array, normal primary human SAECs exposed to C3a, C5a or TGF-β caused discrete and overlapping miRNA regulation related to epithelial proliferation or apoptosis (miR-891A, miR-4442, miR-548, miR-4633), cellular contractility (miR-1197) and lung fibrosis . Our studies present potential mechanisms by which TGF-β activates complement and promotes lung fibrosis.

Arginine Methylation of Hepatic hnRNP H Suppresses Complement Activation and Systemic Inflammation in Alcohol‐Fed Mice

“…We hypothesized that increased systemic inflammation is due to the elevated complement C3a and C5a levels, as both C3a and C5a can act as chemokines and were previously reported to promote inflammation in lung and kidneys. (29)(30)(31)(32) To test this hypothesis, we injected knockout mice either with vehicle control or small molecule inhibitors of C3aR or C5aR receptors twice weekly during duration of alcohol feeding.…”

Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

“…Studies have confirmed that locally synthesized C3 appears to have a stronger influence on rejection than circulating C3 ( 11 ). Other reports have demonstrated that the epithelial and vascular tissues at local sites of inflammation could secrete complement components ( 12 ). Despite Xavier and Cui have demonstrated that complement C3 activation and macrophage infiltration may play important roles in the progression of interstitial fibrosis in UUO mice and human hypertensive nephropathy, the specific mechanism of local synthesis in renal interstitium by immune cells has not been thoroughly investigated ( 13 , 14 ).…”

Potential function and molecular mechanism of circRNAs involved in idiopathic pulmonary fibrosis

“…is involved in the pathogenesis of IPF [30,31], and increased expression of IGFBP5 and ITGB1 plays a vital role in the development of IPF [32,33]. Our present results suggested that up-regulated hsa_circ_0004099 might promote the development of IPF by decreasing the expression of miR-4633 or miR-9, and further increasing the expression of IGFBP5 or ITGB1, respectively.…”