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Exploring PRMT5 Inhibition As a Therapeutic Strategy in Primary and Secondary Hemophagocytic Lymphohistiocytosis

Year: 2025

Type: article

Abstract: Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening autoinflammatory syndrome marked by excessive immune activation, leading to severe tissue damage and multi-organ failure. HLH is classified as primary or secondary. Primary typically affects children and is driven by genetic mutations in the perforin/granzyme genes, disrupting immune system regulation. Secondary HLH affects adults and can be triggered by external factors such as infections, chemotherapies, autoimmunity, or cancer. HLH has high mortality rates due to delayed diagnosis, difficulty identifying the underlying trigger, and limited treatment options. Existing therapies, including etoposide, corticosteroids, JAK/STAT inhibitors, and cytokine-targeting monoclonal antibodies, offer variable efficacy and significant toxicity, highlighting the need for novel treatments. This study investigated the role of protein arginine methyltransferase 5 (PRMT5) in the pathophysiology of primary and secondary HLH. PRMT5 is an enzyme that regulates immune responses via symmetric arginine methylation and is overexpressed in inflammatory conditions. In a perforin-deficient C57bl6 mouse model of primary HLH, we examined the effect of PRMT5 inhibition on immune cell populations and cytokine production. HLH was induced by lymphocytic choriomeningitis virus infection, and PRMT5 activity was inhibited using PRT808 in the primary model. Splenocytes were then analyzed by flow cytometry, and IFNγ levels were measured. For the murine model of secondary HLH, C57bl6 mice were induced by CpG 1826 and anti-IL-10 mAb injections. PRMT5 activity was inhibited using PRT382 and we subsequently compared these effects to the standard JAK/STAT inhibitor ruxolitinib. In the primary HLH model, PRMT5 inhibition significantly reduced the expansion of CD8 T cells (p<0.05), total myeloid cells (CD11b+, p<0.0001), and monocytes (CD11b+ Ly6C+ Ly6G-, p<0.05). IFNγ levels, elevated 10,000-fold in HLH mice compared to controls, were also significantly reduced after PRMT5 inhibition (p<0.01). In the secondary HLH model, PRMT5 inhibition led to reductions in splenomegaly (p<0.0001) and hepatomegaly (p<0.0001), along with decreases in monocytes, neutrophils, and pro-inflammatory cytokines such as IFNγ, IL-6, and IL-18 (p<0.05). The efficacy of PRMT5 inhibition surpassed that of ruxolitinib, normalizing immune cell populations and restoring CD4 T-cell counts to control levels. Our findings suggest PRMT5 plays a pivotal role in the inflammatory processes driving both primary and secondary HLH. By inhibiting PRMT5, it may be possible to develop more effective therapies that reduce the hyperinflammation driving HLH, offering a novel therapeutic approach for this deadly syndrome. Further research into PRMT5 inhibition in human HLH is warranted, as it could significantly improve patient outcomes.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.244