Inflammasomes serve as sensors of infection and cellular stress. Although studies of murine inflammasomes have shed key insights on their human counterpart, the regulation and components differ between mouse and human. For instance, the mouse genome contains homologs of human NLRP1 but not CARD8. However, studying human inflammasomes in vivo remains technically prohibitive. DPP9 is a negative regulator of human NLRP1 and CARD8, and patients with DPP9 deficiency exhibit pancytopenia and other immune-associated defects. However, Dpp9 deletion in conventional laboratory mouse strains do not recapitulate the loss of hematopoietic cells seen in patients, suggesting specie-specific functions. We study human DPP9 deficiency using a humanized mouse model called MISTRG6, which enables the development of human immune system after engraftment with primary human hematopoietic stem and progenitor cells (HSPCs). Using CRISPR editing approaches, we efficiently knock out DPP9 in human HSPCs and found that DPP9 deficiency led to pancytopenia due to the loss of human stem cells in vivo. We then sought to identify the inflammasome involved and found that CARD8 activation induced loss of human HSPCs, since simultaneous CARD8 and DPP9 deletion rescued pancytopenia and HSPC loss. In contrast, NLRP1 was dispensable for DPP9-induced pancytopenia. HSPCs undergo pyroptosis since concurrent caspase-1 deletion also rescues DPP9-/- HSPCs. Taken together, we identify a novel regulatory pathway of human hematopoiesis by a human-specific inflammasome, and find potential therapeutic targets for patients with DPP9 deficiency.

Disclosures

No relevant conflicts of interest to declare.

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