ABSTRACT
Systemic sclerosis (SSc) is a chronic immune-mediated disease characterized by microangiopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Though not fully understood, the pathogenesis of SSc is dominated by microvascular injury, endothelial dysregulation, and immune response that are thought to be associated with fibroblast activation and related fibrogenesis. Among the main clinical subsets, diffuse SSc (dSSc) is a progressive form with rapid and disseminated skin thickening accompanied by internal organ fibrosis and dysfunction. Despite recent advances and multiple randomized clinical trials in early dSSc patients, an effective disease-modifying treatment for progressive skin fibrosis is still missing, and there is a crucial need to identify new targets for therapeutic intervention. Eotaxin-2 (CCL24) is a chemokine secreted by immune cells and epithelial cells, which promotes trafficking of immune cells and activation of pro-fibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the skin and sera of patients with SSc compared with healthy controls; elevated levels of CCL24 and CCR3 were associated with fibrosis and predictive of greater lung function deterioration. Growing evidence supports the potency of a CCL24-blocking antibody as an anti-inflammatory and anti-fibrotic modulating agent in multiple preclinical models that involve liver, skin, and lung inflammation and fibrosis. This review highlights the role of CCL24 in orchestrating immune, vascular, and fibrotic pathways, and the potential of CCL24 inhibition as a novel treatment for SSc.
ABSTRACT
Cerebrovascular amyloidosis caused by amyloid accumulation in blood vessel walls may lead to hemorrhagic stroke and cognitive impairment. Expression of TGF-ß1 under glial fibrillary acidic protein promoter in mice leads to age-related deposition of amyloid, including ß-amyloid (Aß), around cerebral blood vessels, leading to vascular pathology starting at age of 7 months. We have recently shown the important role of macrophages in clearing cerebrovascular amyloid. Scavenger receptor A (SRA) is a multi-ligand and multifunctional receptor expressed on macrophages, and it has been suggested to play a role in meditating phagocytosis of different types of antigens. We investigated the role of SRA in mediating cerebrovascular amyloid clearance. We bred TGF-ß1 mice with SRA(-/-) mice and discovered that TGF-ß1/SRA(-/-) mice showed cerebrovascular pathology at an earlier age (3 months) compared with TGF-ß1 mice. Furthermore, SRA deficiency in macrophages led to impaired clearing of congophilic cerebrovascular amyloid from amyloid precursor protein mouse model and led to reduced phagocytosis of both soluble and insoluble Aß in vivo as compared with macrophages from wild-type mice. Our findings demonstrate the important role of SRA in cerebrovascular amyloid pathology and suggest targeting SRA for future diagnostic and therapeutic approaches for cerebral amyloid angiopathy.
