Siglec14-TLR2 axis mediates anti-HIV-1 immunity in macrophages

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-09-24 DOI:10.1016/j.intimp.2025.115595

Minjuan Shi , Beibei Lu , Wudi Wei , Shanshan Chen , Jie Liu , Xi Hu , Rongfeng Chen , Zongxiang Yuan , Jinming Su , Xiu Chen , Qiao Tang , Yuting Wu , Li Ye , Hao Liang , Junjun Jiang

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Abstract

HIV-exposed seronegative (HESN) individuals exhibit natural resistance to HIV-1 infection, providing a unique model to identify host factors that confer protection against the virus. Building upon our previous transcriptomic studies identifying Siglec14 as a key correlate of HIV-1 resistance in HESN individuals, we investigated its functional role in HIV-1 pathogenesis. We found that HIV-1 infection upregulates Siglec14 in macrophages, where it suppresses viral replication through potent antiviral activity. Mechanistically, Siglec14 directly interacts with HIV-1 Nef protein and subsequently engages TLR2, triggering phosphorylation and activation of NF-κB p65 and IRF3. This dual signaling cascade initiates robust antiviral responses via (1) NF-κB-mediated production of proinflammatory chemokines (CXCLs), and (2) IRF3-dependent induction of type I interferons (e.g., IFN-β) and interferon-stimulated genes (ISGs). Our results establish Siglec14 as a critical innate immune sensor that orchestrates antiviral defenses through TLR2-mediated signaling, highlighting its potential as a therapeutic target for HIV immunotherapy and vaccine development.

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Siglec14-TLR2轴介导巨噬细胞抗hiv -1免疫

hiv暴露血清阴性（HESN）个体表现出对HIV-1感染的天然抗性，为识别赋予抗病毒保护的宿主因素提供了独特的模型。在我们之前的转录组学研究的基础上，我们确定了Siglec14是HESN个体中HIV-1抗性的关键相关因素，我们研究了它在HIV-1发病机制中的功能作用。我们发现HIV-1感染上调巨噬细胞中的Siglec14，通过有效的抗病毒活性抑制病毒复制。机制上，Siglec14直接与HIV-1 Nef蛋白相互作用，随后参与TLR2，触发NF-κB p65和IRF3的磷酸化和激活。这种双信号级联通过(1)NF-κ b介导的促炎趋化因子（CXCLs）的产生，以及(2)irf3依赖的I型干扰素（如IFN-β）和干扰素刺激基因（ISGs）的诱导，启动了强大的抗病毒反应。我们的研究结果表明，Siglec14是一种关键的先天免疫传感器，通过tlr2介导的信号传导协调抗病毒防御，突出了其作为HIV免疫治疗和疫苗开发的治疗靶点的潜力。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.