Abstract：
Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are scavenger receptors expressed by liver sinusoidal endothelial cells (LSECs). The Stabilin-mediated scavenging function is responsible for regulating the molecular composition of circulating blood in mammals. Stab1 and Stab2 have been shown to influence fibrosis in liver and kidneys and to modulate inflammation in atherosclerosis. In this context, circulating and localized TGFBi and POSTN are differentially controlled by the Stabilins as their receptors. To assess Stab1 and Stab2 functions in inflammatory and fibrotic skin disease, topical Imiquimod (IMQ) was used to induce psoriasis-like skin lesions in mice and Bleomycin (BLM) was applied subcutaneously to induce scleroderma-like effects in the skin. The topical treatment with IMQ, as expected, led to psoriasis-like changes in the skin of mice, including increased epidermal thickness and significant weight loss. Clinical severity was reduced in Stab2-deficient compared to Stab1-deficient mice. We did not observe differential effects in the skin of Stabilin-deficient mice after bleomycin injection. Interestingly, treatment with IMQ led to a significant increase of Stabilin ligand TGFBi plasma levels in Stab2-/- mice, treatment with BLM resulted in a significant decrease in TGFBi levels in Stab1-/- mice. Overall, Stab1 and Stab2 deficiency resulted in minor alterations of the disease phenotypes accompanied by alterations of circulating ligands in the blood in response to the disease models. Stabilin-mediated clearance of TGFBi was altered in these disease processes. Taken together our results suggest that Stabilin deficiency-associated plasma alterations may interfere with preclinical disease severity and treatment responses in patients.
摘要：
稳定蛋白-1(Stab1)和稳定蛋白-2(Stab2)是由肝窦内皮细胞(LSEC)表达的清道夫受体。稳定剂介导的清除功能负责调节哺乳动物循环血液的分子组成。Stab1和Stab2已显示影响肝脏和肾脏的纤维化并调节动脉粥样硬化中的炎症。在这种情况下，循环和局部的TGFBi和POSTN受到作为其受体的稳定剂的不同控制。为了评估Stab1和Stab2在炎性和纤维化皮肤病中的功能，局部应用咪喹莫特(IMQ)诱导小鼠银屑病样皮肤损伤,皮下应用博来霉素(BLM)诱导皮肤硬皮病样效应.用IMQ的局部治疗，正如预期的那样，导致小鼠皮肤的牛皮癣样变化，包括表皮厚度增加和明显的体重减轻。与Stab1缺陷小鼠相比，Stab2缺陷小鼠的临床严重程度降低。在博来霉素注射后，我们没有观察到Stabilin缺陷小鼠皮肤的不同作用。有趣的是,用IMQ治疗导致Stab2-/-小鼠中稳定蛋白配体TGFBi血浆水平显着增加，用BLM治疗导致Stab1-/-小鼠中TGFBi水平的显著降低。总的来说,Stab1和Stab2缺乏导致疾病表型的微小改变,伴随着响应于疾病模型的血液中循环配体的改变。稳定蛋白介导的TGFBi清除在这些疾病过程中发生了改变。综上所述，我们的结果表明，与Stabolin缺乏症相关的血浆改变可能会干扰患者的临床前疾病严重程度和治疗反应。
