Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses
Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses
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DOI：
10.1111/cei.13017
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发表时间：
2017-11-01
影响因子：
4.6
通讯作者：
Luo, X. M.
中科院分区：
文献类型：
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作者：
Liao, X.;Ren, J.;Luo, X. M.
狼疮性肾炎（LN）是系统性红斑狼疮（SLE）的主要表现，导致40-60%的SLE患者发病和死亡。LN的发病机制尚不完全清楚。最近的研究表明，在SLE患者和狼疮易感小鼠的狼疮肾炎肾脏中存在各种免疫细胞群。这些细胞可能在原位发挥重要的致病或调节作用，以促进或维持LN。在这里，我们使用狼疮易感小鼠模型，显示肾脏浸润的CD 11 c（+）髓样细胞群在LN中的致病作用。随着LN的进展，这些CD 11 c（+）细胞在狼疮倾向小鼠的肾脏中积累。该群体的表面标志物表明其树突状细胞身份和从淋巴细胞抗原6复合物（Ly 6C）（低）成熟单核细胞分化。这些肾脏浸润性CD 11 c（+）细胞的细胞因子/趋化因子谱表明它们在促进LN中的作用，这在功能丧失体内研究中通过使用靶向CX（3）CR 1（在这些CD 11 c（+）细胞上高度表达的趋化因子受体）的抗体-药物缀合物（ADC）策略进一步证实。然而，CX（3）CR 1在将CD 11 c（+）细胞归巢到狼疮肾炎肾中方面是不确定的。最后，我们发现这些CD 11 c（+）细胞与肾脏中的浸润性T细胞共定位。使用离体共培养系统，我们发现肾脏浸润性CD 11 c（+）细胞促进肾脏浸润性CD 4（+）T细胞的存活、增殖和干扰素产生，提示这些CD 11 c（+）细胞促进LN的T细胞依赖性机制。总之，我们的研究结果确定了一个致病的肾脏浸润CD 11 c（+）细胞群促进LN的进展，这可能是一个新的治疗LN的治疗靶点。
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)(low) 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(3)CR1, a chemokine receptor expressed highly on these CD11c(+) cells. However, CX(3)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-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.