Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

Abstract

BackgroundThe balancing functions of pro/anti-inflammatory mediators of the complex innate responses have been investigated in a variety of experimental inflammatory settings. Annexin-A1 (AnxA1) is one mediator of endogenous anti-inflammation, affording regulation of leukocyte trafficking and activation in many contexts, yet its role in lung pathologies has been scarcely investigated, despite being highly expressed in lung cells. Here we have applied the bleomycin lung fibrosis model to AnxA1 null mice over a 21-day time-course, to monitor potential impact of this mediator on the control of the inflammatory and fibrotic phases.ResultsAnalyses in wild-type mice revealed strict spatial and temporal regulation of the Anxa1 gene, e.g. up-regulation in epithelial cells and infiltrated granulocytes at day 7, followed by augmented protein levels in alveolar macrophages by day 21. Absence of AnxA1 caused increases in: i) the degree of inflammation at day 7; and ii) indexes of fibrosis (assessed by deposition of hydroxyproline in the lung) at day 7 and 21. These alterations in AnxA1 null mice were paralleled by augmented TGF-β1, IFN-γ and TNF-α generation compared to wild-type mice. Finally, treatment of wild type animals with an AnxA1 peptido-mimetic, given prophylactically (from day 0 to 21) or therapeutically (from day 14 onward), ameliorated both signs of inflammation and fibrosis.ConclusionCollectively these data reveal a pathophysiological relevance for endogenous AnxA1 in lung inflammation and, more importantly, fibrosis, and may open new insights for the pharmacological treatment of lung fibrosis.

Annexins – insights from knockout mice

“…Strikingly, and supporting earlier in vivo studies with recombinant AnxA1 tools (Perretti and Dalli, 2009;Sugimoto et al, 2016), AnxA1 -/-mice displayed a boosted immune response. This was characterized by an increased leucocyte migratory behavior and Croxtall et al, 2003;Hannon et al, 2003;Damazo et al, 2011;Drechsler et al, 2015reviewed in D'Acquisto et al, 2008Perretti and D'Acquisto, 2009;Perretti and Dalli, 2009;Gavins and Hickey, 2012;Yang et al, 2013a;Sugimoto et al, 2016Nair et al, 2015Yang et al 2013breviewed in D'Acquisto et al, 2008Perretti and D'Acquisto, 2009;Perretti and Dalli, 2009;Gavins and Hickey, 2012;Yang et al, 2013a;Sugimoto et al, 2016 Wound (Hannon et al, 2003). Altogether, this prominent extracellular AnxA1 activity suggested the existence of an AnxA1 receptor.…”

“…In addition, AnxA1 deficiency is detrimental in epithelial wound repair (Leoni et al, 2013). Loss of AnxA1 also has a role in lung fibrosis (Damazo et al, 2011), obesity and insulin resistance (Akasheh et al, 2013), as well as adrenal steroidogenesis in sepsis (Buss et al, 2015) or allergic conjunctivitis (Gimenes et al, 2015). Given the limitations of peptide delivery for therapeutic use in vivo, efforts have been made to develop small molecule AnxA1 mimetics.…”

Annexin A1: shifting the balance towards resolution and repair

“…While ANXA1 biosynthesis and release can be induced by the pro-fibrotic cytokine TGF-β, ANXA1 inhibits the cytokine effects on α -SMA and collagen A1 gene expression. In synovial fibroblasts from patients with rheumatoid arthritis, ANXA1 enhanced secretion of matrix metalloproteinase 1, an enzyme involved in the degradation of extracellular matrix components (Damazo et al , 2011; Morand et al , 2006; Tagoe et al , 2008). Furthermore, ANXA1 absence in mice is associated with aggravated bleomycin-induced pulmonary fibrosis (Damazo et al , 2011).…”

“…In synovial fibroblasts from patients with rheumatoid arthritis, ANXA1 enhanced secretion of matrix metalloproteinase 1, an enzyme involved in the degradation of extracellular matrix components (Damazo et al , 2011; Morand et al , 2006; Tagoe et al , 2008). Furthermore, ANXA1 absence in mice is associated with aggravated bleomycin-induced pulmonary fibrosis (Damazo et al , 2011). Thus, this ligand–receptor interaction may represent a novel therapeutic target to inhibit fibrosis in chronic kidney disease (Neymeyer et al , 2015).…”

Annexin‐A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin‐resistant, but not insulin‐deficient, mice

“…It is an important second messenger for glucocorticoids and mediates many of their anti‐inflammatory actions (Perretti & D'Acquisto, ). Mice deficient in AnxA1 exhibit an exaggerated response to many inflammatory disorders, including pulmonary fibrosis (Damazo et al, ), rheumatoid arthritis (Yang et al, ), stroke (Gavins, Dalli, Flower, Granger, & Perretti, ), and endotoxemia (Damazo et al, ; Qin et al, ). This is consistent with our previous observations that exogenous AnxA1 preserves myocardial function in ischaemia–reperfusion injury in vitro (Qin et al, ; Ritchie, Gordon, Woodman, Cao, & Dusting, ; Ritchie, Sun, Bilszta, Gulluyan, & Dusting, ).…”