Scindia Yogesh, Wlazlo Ewa, Ghias Elizabeth, Cechova Sylvia, Loi Valentina, Leeds Joseph, Ledesma Jonathan, Helen Cathro, Swaminathan Sundararaman
Division of Nephrology, Center for Immunity, Inflammation and Regeneration, University of Virginia, Charlottesville, Virginia, USA.
Division of Nephrology, Center for Immunity, Inflammation and Regeneration, University of Virginia, Charlottesville, Virginia, USA.
Kidney Int. 2020 Jul;98(1):100-115. doi: 10.1016/j.kint.2020.01.025. Epub 2020 Feb 17.
Lupus nephritis is the end organ manifestation of systemic lupus erythematosus. Iron metabolism and its master regulator, hepcidin, are known to regulate cell proliferation and inflammation, but their direct role in the pathophysiology of lupus nephritis remains under-investigated. Exogenous hepcidin reduced the severity of lupus nephritis in MRL/lpr mice, a preclinical model of spontaneous systemic lupus erythematosus without worsening anemia of inflammation. Hepcidin treatment reduced renal iron accumulation, systemic and intrarenal cytokines, and renal immune cell infiltration, independent of glomerular immune complex deposits and circulating autoantibodies. Hepcidin increased renal H-ferritin (a ferroxidase), reduced expression of free iron dependent DNA synthesis enzymes, Ribonucleotide Reductase 1 and 2, and intra-renal macrophage proliferation. These findings were recapitulated in vitro upon treatment of macrophages with hepcidin and murine colony stimulation factor-1. Furthermore, hepcidin-treated macrophages secreted less IL-1β and IL-6 upon stimulation with the TLR3 agonist polyinosine-polycytidylic acid. Of clinical relevance, hepcidin reduced progression and severity of nephritis in old mice with established systemic autoimmunity and overt proteinuria, highlighting its therapeutic potential. Thus, our findings provide a proof-of-concept that targeting cellular iron metabolism with hepcidin represents a promising therapeutic strategy in lupus nephritis.
狼疮性肾炎是系统性红斑狼疮的终末器官表现。铁代谢及其主要调节因子铁调素已知可调节细胞增殖和炎症，但其在狼疮性肾炎病理生理学中的直接作用仍未得到充分研究。外源性铁调素可减轻MRL/lpr小鼠（一种自发性系统性红斑狼疮的临床前模型）的狼疮性肾炎严重程度，且不会加重炎症性贫血。铁调素治疗可减少肾脏铁蓄积、全身和肾脏内的细胞因子以及肾脏免疫细胞浸润，与肾小球免疫复合物沉积和循环自身抗体无关。铁调素可增加肾脏H-铁蛋白（一种铁氧化酶），降低游离铁依赖性DNA合成酶核糖核苷酸还原酶1和2的表达以及肾脏内巨噬细胞增殖。在用铁调素和小鼠集落刺激因子-1处理巨噬细胞后，这些结果在体外得到了重现。此外，在用Toll样受体3激动剂聚肌苷酸-聚胞苷酸刺激后，经铁调素处理的巨噬细胞分泌的白细胞介素-1β和白细胞介素-6较少。具有临床相关性的是，铁调素可降低已建立系统性自身免疫和明显蛋白尿的老年小鼠肾炎的进展和严重程度，突出了其治疗潜力。因此，我们的研究结果提供了一个概念验证，即靶向细胞铁代谢的铁调素在狼疮性肾炎中代表了一种有前景的治疗策略。
