Brown-Burke Fiona, Saadey Rachel, Mao Hsiao-Yin Charlene, Marra Paola, Brooks Eric, Wandtke Alexa, Hout Ian, Leon Sydney, Sharma Archisha, Yasin Aneeq, Cash Taylor, Ahmed Elshafa Hassan, Baiocchi Ethan, Finoti Stephanie, Zhang Xiaoli, Bhagwat Neha, Vaddi Kris, Scherle Peggy, Mozhenkova Anna, El-Ayachi Ikbale, Schenk Austin D, Sloan Shelby L, Whitman Kaylee, Helmig-Mason JoBeth, Steyn Sheldon, Klimaszewski Haley L, Weist Jessica, Weigel Christoph, Koirala Shirsha, Alinari Lapo, Snyder Katiri, Ranganathan Parvathi, Chen Chia-Jo, Jordan Michael B, Baiocchi Robert A, Shindiapina Polina
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH.
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH.
Blood Adv. 2025 May 27;9(10):2379-2392. doi: 10.1182/bloodadvances.2024013651.
Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially lethal hyperinflammatory syndrome characterized by pathologic immune activation and excessive production of proinflammatory cytokines leading to tissue damage and multisystem organ failure. There is an urgent need for the discovery of novel targets and development of therapeutic strategies to treat this rare but deadly syndrome. Protein arginine methyltransferase 5 (PRMT5) mediates T-cell-based inflammatory responses, making it a potential actionable target for the treatment of HLH. Using CPG-1826 and anti-interleukin-10R (IL-10R) antibody, we induced murine secondary HLH in vivo with a marked expansion of splenic myeloid cell subsets and concurrent reduction of T- and natural killer (NK)-cell populations. PRMT5 expression was significantly upregulated in splenic T and NK lymphocytes, monocytes, and dendritic cells in mice with HLH (P < .05). Treatment with PRT382, a potent and selective PRMT5 inhibitor, significantly reduced physical signs of secondary HLH, including splenomegaly, hepatomegaly, and anemia (P < .0001 in each case), when compared with untreated mice. Inflammatory cytokines known to drive hyperinflammation in HLH, including interferon-γ and IL-6 were reduced to healthy levels with PRT382 treatment (P > .999 for both). PRT382 treatment also reduced the expansion of myeloid cell populations (P < .0001) in mice with HLH, compared with untreated mice, while restoring T- and NK-cell numbers (P < .001 for both). These results identify PRMT5 as a promising target for the management of secondary HLH and justify further exploration in this and other models of hyperinflammation.
噬血细胞性淋巴组织细胞增生症（HLH）是一种罕见但具有侵袭性且可能致命的高炎症综合征，其特征为病理性免疫激活和促炎细胞因子过度产生，导致组织损伤和多系统器官衰竭。迫切需要发现新的靶点并开发治疗策略来治疗这种罕见但致命的综合征。蛋白质精氨酸甲基转移酶5（PRMT5）介导基于T细胞的炎症反应，使其成为治疗HLH的潜在可作用靶点。使用CPG - 1826和抗白细胞介素10受体（IL - 10R）抗体，我们在体内诱导了小鼠继发性HLH，脾脏髓样细胞亚群显著扩增，同时T细胞和自然杀伤（NK）细胞群体减少。HLH小鼠脾脏中的T淋巴细胞、NK淋巴细胞、单核细胞和树突状细胞中PRMT5表达显著上调（P <.05）。与未治疗的小鼠相比，用强效选择性PRMT5抑制剂PRT382治疗可显著减轻继发性HLH的体征，包括脾肿大、肝肿大和贫血（每种情况P <.0001）。已知在HLH中驱动高炎症的炎性细胞因子，包括干扰素 - γ和IL - 6，经PRT382治疗后降至健康水平（两者P >.999）。与未治疗的小鼠相比，PRT382治疗还减少了HLH小鼠髓样细胞群体的扩增（P <.0001），同时恢复了T细胞和NK细胞数量（两者P <.001）。这些结果表明PRMT5是继发性HLH治疗的一个有前景靶点，并证明在该模型和其他高炎症模型中进行进一步探索是合理的。
