Dos Santos Plinio Marcos Freire, Díaz Acosta Chyntia Carolina, Rosa Thabatta Leal Silveira Andrezo, Ishiba Michelle Harumi, Dias André Alves, Pereira Antonio Marcos Rodrigues, Gutierres Luísa Domingos, Pereira Melissa Pontes, da Silva Rocha Matheus, Rosa Patrícia Sammarco, Bertoluci Daniele F F, Meyer-Fernandes José Roberto, da Mota Ramalho Costa Fabricio, Marques Maria Angela M, Belisle John T, Pinheiro Roberta Olmo, Rodrigues Luciana Silva, Pessolani Maria Cristina Vidal, Berrêdo-Pinho Marcia
Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, San Lorenzo, Paraguay.
Front Pharmacol. 2024 Jun 28;15:1399363. doi: 10.3389/fphar.2024.1399363. eCollection 2024.
Leprosy is a chronic infectious disease caused by , which can lead to a disabling neurodegenerative condition. preferentially infects skin macrophages and Schwann cells-glial cells of the peripheral nervous system. The infection modifies the host cell lipid metabolism, subverting it in favor of the formation of cholesterol-rich lipid droplets (LD) that are essential for bacterial survival. Although researchers have made progress in understanding leprosy pathogenesis, many aspects of the molecular and cellular mechanisms of host-pathogen interaction still require clarification. The purinergic system utilizes extracellular ATP and adenosine as critical signaling molecules and plays several roles in pathophysiological processes. Furthermore, nucleoside surface receptors such as the adenosine receptor AR involved in neuroimmune response, lipid metabolism, and neuron-glia interaction are targets for the treatment of different diseases. Despite the importance of this system, nothing has been described about its role in leprosy, particularly adenosinergic signaling (AdoS) during -Schwann cell interaction.
was purified from the hind footpad of athymic mice. ST88-14 human cells were infected with in the presence or absence of specific agonists or antagonists of AdoS. Enzymatic activity assays, fluorescence microscopy, Western blotting, and RT-qPCR analysis were performed. viability was investigated by RT-qPCR, and cytokines were evaluated by enzyme-linked immunosorbent assay.
We demonstrated that -infected Schwann cells upregulated CD73 and ADA and downregulated AR expression and the phosphorylation of the transcription factor CREB (p-CREB). On the other hand, activation of AR with its selective agonist, CGS21680, resulted in: 1) reduced lipid droplets accumulation and pro-lipogenic gene expression; 2) reduced production of IL-6 and IL-8; 3) reduced intracellular viability; 4) increased levels of p-CREB.
These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that , by downmodulating the expression and activity of AR in Schwann cells, decreases AR downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus.
麻风病是一种由[病原体名称未给出]引起的慢性传染病，可导致致残性神经退行性疾病。[病原体名称未给出]优先感染皮肤巨噬细胞和外周神经系统的施万细胞 - 神经胶质细胞。这种感染会改变宿主细胞的脂质代谢，使其有利于形成富含胆固醇的脂滴（LD），而脂滴对细菌存活至关重要。尽管研究人员在理解麻风病发病机制方面取得了进展，但宿主 - 病原体相互作用的分子和细胞机制的许多方面仍需阐明。嘌呤能系统利用细胞外ATP和腺苷作为关键信号分子，并在病理生理过程中发挥多种作用。此外，参与神经免疫反应、脂质代谢和神经元 - 神经胶质细胞相互作用的核苷表面受体，如腺苷受体AR，是治疗不同疾病的靶点。尽管该系统很重要，但关于其在麻风病中的作用，特别是在[病原体名称未给出] - 施万细胞相互作用期间的腺苷能信号传导（AdoS），尚无相关描述。
[病原体名称未给出]从无胸腺小鼠的后足垫中纯化出来。在存在或不存在AdoS特异性激动剂或拮抗剂的情况下，用[病原体名称未给出]感染ST88 - 14人细胞。进行酶活性测定、荧光显微镜检查、蛋白质印迹和RT - qPCR分析。通过RT - qPCR研究[病原体名称未给出]的活力，并通过酶联免疫吸附测定评估细胞因子。
我们证明，感染[病原体名称未给出]的施万细胞上调了CD73和ADA，并下调了AR表达以及转录因子CREB的磷酸化（p - CREB）。另一方面，用其选择性激动剂CGS21680激活AR导致：1）脂滴积累和促脂肪生成基因表达减少；2）IL - 6和IL - 8产生减少；3）细胞内[病原体名称未给出]活力降低；4）p - CREB水平升高。
这些发现表明AdoS参与了麻风病神经发病机制，并支持这样的观点，即[病原体名称未给出]通过下调施万细胞中AR的表达和活性，降低AR下游信号传导，有助于维持脂滴积累和杆菌的细胞内活力。
