Tamoxifen-inducible Pld3 Pld4 knockout mouse model as an animal model for secondary HLH and its treatment 2027

Description Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by multisystem inflammation resulting from prolonged excessive activation of antigen-presenting cells. A commonly used HLH animal model involves LCMV infection in perforin mutant mice. Although this model is useful for understanding HLH pathophysiology, it presents a challenge in determining if the immunopathology results from the infections required to trigger HLH, or the HLH itself. Phospholipases D3 and D4 (PLD3, PLD4) are single stranded exonucleases localized in endolysosomes, which digest ssRNA and ssDNA, and limit cellular response to toll-like receptor ligands. Mice deficient in both PLD3 and PLD4 have elevated cytokines and hepatosplenomegaly and die before weaning age due to HLH. The model illustrates that nucleic overload alone can trigger HLH. But the early lethality of the model limits their use of as an animal model of HLH and for testing HLH treatments. We therefore generated tamoxifen-inducible Pld3-/- Pld4fl/fl ERT2Cre+ mice and propose them for use as a secondary HLH animal model. Our results show that following tamoxifen administration, Pld3-/- Pld4fl/fl ERT2Cre+ mice exhibit severe hepatosplenomegaly, lymphopenia, and systemic inflammation, which recapitulate known HLH characteristics. We are currently investigating the disease drivers and efficacy of drug inhibitors, as well as assessing recombinant PLD3 protein as a treatment for HLH and other autoimmune mouse models.