Singh Neetu, Sundar Shyam
Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
Mol Immunol. 2017 May;85:111-119. doi: 10.1016/j.molimm.2017.02.008. Epub 2017 Feb 20.
Chemokines play an important role in determining cellular composition at inflammatory sites, and as such, influence disease outcome. In this study, we investigated the expression profile and splenic cellular source of various inflammatory chemokines and their receptors in human visceral leishmaniasis (VL). The expression of chemokines or their receptors was measured at the gene and protein level by employing real time qPCR and a cytometric bead array assay, respectively. In addition, the cellular source of chemokines and their receptors in the spleen was identified employing gene expression analyses in sequentially selected cell subsets. We identified elevated expression of CXCL10, CXCL9, CXCL8, and decreased CCL2 from VL patients. Further, we found reduced expression of the chemokine receptors CXCR1, CXCR2, CXCR3 and CCR2, but increased expression of CCR7 on VL PBMC, compared to endemic healthy controls. Additionally, splenic monocytes were found to be the major source of CXCL10, CXCL9 and CCR2, whereas T cells were the main source of CXCR3 and CCR7. We also report a strong association between plasma IFN-γ and CXCL-10, CXCL-9 levels. Enhanced parasite burden positively correlates with increased expression of CXCL10, CXCL9, IFN-γ and IL-10. Overall our result indicates that VL patients have an elevated inflammatory chemokine milieu which correlated with disease severity. However, expression of their chemokine receptors was significantly impaired, which may have contributed to reduced frequencies of blood monocytes and neutrophils in peripheral blood. In contrast, enhanced expression of CCR7 was associated with increased numbers of activated T cells in circulation. These findings highlight the importance of chemokines for recruitment of various cell populations in VL, and the knowledge gained may help in global understandings of the complex interaction between chemokines and pathological processes, and therefore will contribute towards the design of novel chemokine based immunological therapies against VL.
趋化因子在决定炎症部位的细胞组成方面发挥着重要作用，因此会影响疾病的转归。在本研究中，我们调查了各种炎症趋化因子及其受体在人类内脏利什曼病（VL）中的表达谱和脾脏细胞来源。分别采用实时定量PCR和细胞计数珠阵列分析在基因和蛋白质水平上检测趋化因子或其受体的表达。此外，通过对依次选择的细胞亚群进行基因表达分析，确定了脾脏中趋化因子及其受体的细胞来源。我们发现VL患者的CXCL10、CXCL9、CXCL8表达升高，CCL2表达降低。此外，与地方性健康对照相比，我们发现VL患者外周血单个核细胞（PBMC）上趋化因子受体CXCR1、CXCR2、CXCR3和CCR2的表达降低，但CCR7的表达增加。此外，发现脾脏单核细胞是CXCL10、CXCL9和CCR2的主要来源，而T细胞是CXCR3和CCR7的主要来源。我们还报告了血浆干扰素-γ与CXCL-10、CXCL-9水平之间存在强关联。寄生虫负荷增加与CXCL10、CXCL9、干扰素-γ和白细胞介素-10表达增加呈正相关。总体而言，我们的结果表明VL患者具有升高的炎症趋化因子环境，这与疾病严重程度相关。然而，其趋化因子受体的表达明显受损，这可能导致外周血中血液单核细胞和中性粒细胞的频率降低。相反，CCR7表达增加与循环中活化T细胞数量增加有关。这些发现突出了趋化因子在VL中招募各种细胞群体的重要性，所获得的知识可能有助于全面了解趋化因子与病理过程之间的复杂相互作用，因此将有助于设计基于趋化因子的新型抗VL免疫疗法。
