Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States of America.
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
PLoS Pathog. 2019 Jul 1;15(7):e1007883. doi: 10.1371/journal.ppat.1007883. eCollection 2019 Jul.
Chronic infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects an estimated 35 million and 75 million individuals worldwide, respectively. These viruses induce persistent inflammation which often drives the development or progression of organ-specific diseases and even cancer including Hepatocellular Carcinoma (HCC). In this study, we sought to examine inflammatory responses following HIV or HCV stimulation of macrophages or Kupffer cells (KCs), that may contribute to virus mediated inflammation and subsequent liver disease. KCs are liver-resident macrophages and reports have provided evidence that HIV can stimulate and infect them. In order to characterize HIV-intrinsic innate immune responses that may occur in the liver, we performed microarray analyses on KCs following HIV stimulation. Our data demonstrate that KCs upregulate several innate immune signaling pathways involved in inflammation, myeloid cell maturation, stellate cell activation, and Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling. TREM1 is a member of the immunoglobulin superfamily of receptors and it is reported to be involved in systemic inflammatory responses due to its ability to amplify activation of host defense signaling pathways. Our data demonstrate that stimulation of KCs with HIV or HCV induces the upregulation of TREM1. Additionally, HIV viral proteins can upregulate expression of TREM1 mRNA through NF-кB signaling. Furthermore, activation of the TREM1 signaling pathway, with a targeted agonist, increased HIV or HCV-mediated inflammatory responses in macrophages due to enhanced activation of the ERK1/2 signaling cascade. Silencing TREM1 dampened inflammatory immune responses elicited by HIV or HCV stimulation. Finally, HIV and HCV infected patients exhibit higher expression and frequency of TREM1 and CD68 positive cells. Taken together, TREM1 induction by HIV contributes to chronic inflammation in the liver and targeting TREM1 signaling may be a therapeutic option to minimize HIV induced chronic inflammation.
慢性人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）感染分别影响全球约 3500 万人和 7500 万人。这些病毒引起持续的炎症，通常导致器官特异性疾病的发展或进展，甚至包括肝细胞癌（HCC）在内的癌症。在这项研究中，我们试图研究巨噬细胞或枯否细胞（KC）受 HIV 或 HCV 刺激后的炎症反应，这些反应可能导致病毒介导的炎症和随后的肝病。KC 是肝脏驻留的巨噬细胞，有报道称 HIV 可以刺激并感染它们。为了描述可能发生在肝脏中的 HIV 固有先天免疫反应，我们在 HIV 刺激后对 KC 进行了微阵列分析。我们的数据表明，KC 上调了几个参与炎症、髓样细胞成熟、星状细胞激活和髓样细胞触发受体 1（TREM1）信号的先天免疫信号通路。TREM1 是免疫球蛋白超家族受体的成员，据报道，由于其能够放大宿主防御信号通路的激活，它参与全身炎症反应。我们的数据表明，HIV 或 HCV 刺激 KC 会诱导 TREM1 的上调。此外，HIV 病毒蛋白可以通过 NF-кB 信号通路上调 TREM1 mRNA 的表达。此外，由于 ERK1/2 信号级联的激活增强，TREM1 信号通路的激活（通过靶向激动剂）增加了巨噬细胞中 HIV 或 HCV 介导的炎症反应。沉默 TREM1 可减弱 HIV 或 HCV 刺激引起的炎症免疫反应。最后，HIV 和 HCV 感染患者表现出更高的 TREM1 和 CD68 阳性细胞的表达和频率。总之，HIV 诱导的 TREM1 有助于肝脏的慢性炎症，靶向 TREM1 信号可能是减轻 HIV 诱导的慢性炎症的一种治疗选择。
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