Increased Susceptibility of Melanin-Concentrating Hormone-Deficient Mice to Infection with Salmonella enterica Serovar Typhimurium
Increased Susceptibility of Melanin-Concentrating Hormone-Deficient Mice to Infection with Salmonella enterica Serovar Typhimurium
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DOI：
10.1128/iai.00572-12
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发表时间：
2013-01-01
影响因子：
3.1
通讯作者：
Kokkotou, Efi
中科院分区：
文献类型：
--
作者：
Karagiannis, Apostolos K. A.;Ziogas, Dimitrios C.;Kokkotou, Efi
黑色素浓缩激素（MCH）最初在哺乳动物中被鉴定为调节食欲和能量平衡的下丘脑神经肽。然而，MCH 受体在外周组织中的广泛分布表明 MCH 的其他功能仍然很大程度上未知。我们之前曾报道，缺乏 MCH 的小鼠在暴露于艰难梭菌毒素 A 时，肠道炎症会减弱。为了进一步表征 MCH 在宿主针对肠道病原体的防御机制中的作用，在 MCH 缺陷小鼠及其野生型同窝小鼠中诱导沙门氏菌小肠结肠炎（使用肠沙门氏菌鼠伤寒血清型）。在缺乏 MCH 的情况下，受感染的小鼠死亡率增加，这与血液、肝脏和脾脏中细菌含量较高有关。此外，由于上皮损伤、免疫细胞浸润以及局部和全身细胞因子水平，基因敲除小鼠出现了更严重的肠道炎症。矛盾的是，MCH 基因敲除小鼠中炎症反应的增强与浸润肠道的巨噬细胞水平不成比例地降低有关。因此，我们研究了 MCH 对单核细胞/巨噬细胞功能的潜在直接影响，这对于防御肠道病原体至关重要。使用表达内源性 MCH 受体的 RAW 264.7 小鼠单核细胞，我们发现 MCH 处理增强了这些细胞的吞噬能力。总而言之，这些发现揭示了 MCH 在宿主-细菌相互作用中的先前未被认识到的作用。
Melanin-concentrating hormone (MCH) was initially identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, the wide distribution of MCH receptors in peripheral tissues suggests additional functions for MCH which remain largely unknown. We have previously reported that mice lacking MCH develop attenuated intestinal inflammation when exposed to Clostridium difficile toxin A. To further characterize the role of MCH in host defense mechanisms against intestinal pathogens, Salmonella enterocolitis (using Salmonella enterica serovar Typhimurium) was induced in MCH-deficient mice and their wild-type littermates. In the absence of MCH, infected mice had increased mortality associated with higher bacterial loads in blood, liver, and spleen. Moreover, the knockout mice developed more-severe intestinal inflammation, based on epithelial damage, immune cell infiltrates, and local and systemic cytokine levels. Paradoxically, these enhanced inflammatory responses in the MCH knockout mice were associated with disproportionally lower levels of macrophages infiltrating the intestine. Hence, we investigated potential direct effects of MCH on monocyte/macrophage functions critical for defense against intestinal pathogens. Using RAW 264.7 mouse monocytic cells, which express endogenous MCH receptor, we found that treatment with MCH enhanced the phagocytic capacity of these cells. Taken together, these findings reveal a previously unappreciated role for MCH in host-bacterial interactions.