Liao X, Ren J, Reihl A, Pirapakaran T, Sreekumar B, Cecere T E, Reilly C M, Luo X M
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA.
Clin Exp Immunol. 2017 Nov;190(2):187-200. doi: 10.1111/cei.13017. Epub 2017 Aug 18.
Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE), causing morbidity and mortality in 40-60% of SLE patients. The pathogenic mechanisms of LN are not completely understood. Recent studies have demonstrated the presence of various immune cell populations in lupus nephritic kidneys of both SLE patients and lupus-prone mice. These cells may play important pathogenic or regulatory roles in situ to promote or sustain LN. Here, using lupus-prone mouse models, we showed the pathogenic role of a kidney-infiltrating CD11c myeloid cell population in LN. These CD11c cells accumulated in the kidneys of lupus-prone mice as LN progressed. Surface markers of this population suggest their dendritic cell identity and differentiation from lymphocyte antigen 6 complex (Ly6C) mature monocytes. The cytokine/chemokine profile of these renal-infiltrating CD11c cells suggests their roles in promoting LN, which was confirmed further in a loss-of-function in-vivo study by using an antibody-drug conjugate (ADC) strategy targeting CX CR1, a chemokine receptor expressed highly on these CD11c cells. However, CX CR1 was dispensable for the homing of CD11c cells into lupus nephritic kidneys. Finally, we found that these CD11c cells co-localized with infiltrating T cells in the kidney. Using an ex- vivo co-culture system, we showed that renal-infiltrating CD11c cells promoted the survival, proliferation and interferon-γ production of renal-infiltrating CD4 T cells, suggesting a T cell-dependent mechanism by which these CD11c cells promote LN. Together, our results identify a pathogenic kidney-infiltrating CD11c cell population promoting LN progression, which could be a new therapeutic target for the treatment of LN.
狼疮性肾炎（LN）是系统性红斑狼疮（SLE）的主要表现形式，导致40%-60%的SLE患者发病和死亡。LN的致病机制尚未完全明确。最近的研究表明，SLE患者和狼疮易感小鼠的狼疮性肾炎肾脏中存在多种免疫细胞群。这些细胞可能在局部发挥重要的致病或调节作用，以促进或维持LN。在此，我们利用狼疮易感小鼠模型，展示了肾脏浸润性CD11c髓样细胞群在LN中的致病作用。随着LN的进展，这些CD11c细胞在狼疮易感小鼠的肾脏中积聚。该细胞群的表面标志物表明它们具有树突状细胞特征，并由淋巴细胞抗原6复合体（Ly6C）成熟单核细胞分化而来。这些肾脏浸润性CD11c细胞的细胞因子/趋化因子谱表明它们在促进LN方面发挥作用，这在一项功能丧失体内研究中通过使用针对CXCR1的抗体药物偶联物（ADC）策略得到进一步证实，CXCR1是这些CD11c细胞上高表达的一种趋化因子受体。然而，CXCR1对于CD11c细胞归巢至狼疮性肾炎肾脏并非必需。最后，我们发现这些CD11c细胞与肾脏中浸润的T细胞共定位。利用体外共培养系统，我们表明肾脏浸润性CD11c细胞促进了肾脏浸润性CD4 T细胞的存活、增殖和干扰素-γ产生，提示这些CD11c细胞通过一种T细胞依赖机制促进LN。总之，我们的结果确定了一种促进LN进展的致病肾脏浸润性CD11c细胞群，这可能是治疗LN的一个新的治疗靶点。
