Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Immunol. 2023 Mar 15;14:1111960. doi: 10.3389/fimmu.2023.1111960. eCollection 2023.
The chemokine network is comprised of a family of signal proteins that encode messages for cells displaying chemokine G-protein coupled receptors (GPCRs). The diversity of effects on cellular functions, particularly directed migration of different cell types to sites of inflammation, is enabled by different combinations of chemokines activating signal transduction cascades on cells displaying a combination of receptors. These signals can contribute to autoimmune disease or be hijacked in cancer to stimulate cancer progression and metastatic migration. Thus far, three chemokine receptor-targeting drugs have been approved for clinical use: Maraviroc for HIV, Plerixafor for hematopoietic stem cell mobilization, and Mogalizumab for cutaneous T-cell lymphoma. Numerous compounds have been developed to inhibit specific chemokine GPCRs, but the complexity of the chemokine network has precluded more widespread clinical implementation, particularly as anti-neoplastic and anti-metastatic agents. Drugs that block a single signaling axis may be rendered ineffective or cause adverse reactions because each chemokine and receptor often have multiple context-specific functions. The chemokine network is tightly regulated at multiple levels, including by atypical chemokine receptors (ACKRs) that control chemokine gradients independently of G-proteins. ACKRs have numerous functions linked to chemokine immobilization, movement through and within cells, and recruitment of alternate effectors like β-arrestins. Atypical chemokine receptor 1 (ACKR1), previously known as the Duffy antigen receptor for chemokines (DARC), is a key regulator that binds chemokines involved in inflammatory responses and cancer proliferation, angiogenesis, and metastasis. Understanding more about ACKR1 in different diseases and populations may contribute to the development of therapeutic strategies targeting the chemokine network.
趋化因子网络由一组信号蛋白组成，这些蛋白编码的信息传递给表达趋化因子 G 蛋白偶联受体（GPCR）的细胞。通过不同的趋化因子组合激活表达不同受体组合的细胞中的信号转导级联，实现了对细胞功能的多样化影响，特别是不同类型的细胞向炎症部位的定向迁移。这些信号可以导致自身免疫性疾病，也可以在癌症中被劫持，以刺激癌症进展和转移迁移。迄今为止，已有三种趋化因子受体靶向药物被批准用于临床使用：Maraviroc 用于 HIV，Plerixafor 用于造血干细胞动员，以及 Mogalizumab 用于皮肤 T 细胞淋巴瘤。已经开发了许多化合物来抑制特定的趋化因子 GPCR，但趋化因子网络的复杂性阻止了更广泛的临床应用，特别是作为抗肿瘤和抗转移药物。阻断单一信号轴的药物可能会失效或引起不良反应，因为每个趋化因子和受体通常具有多个特定于上下文的功能。趋化因子网络在多个水平上受到严格调控，包括通过非典型趋化因子受体（ACKR）来独立于 G 蛋白控制趋化因子梯度。ACKR 具有多种与趋化因子固定、在细胞内外移动以及募集替代效应物（如β-arrestin）相关的功能。非典型趋化因子受体 1（ACKR1），以前称为趋化因子 Duffy 抗原受体（DARC），是一种关键的调节剂，它结合参与炎症反应和癌症增殖、血管生成和转移的趋化因子。在不同疾病和人群中更多地了解 ACKR1 可能有助于开发针对趋化因子网络的治疗策略。
