The NLRP1 inflammasome is activated upon viral infection or danger-associated signals, resulting in secretion of pro-inflammatory cytokines IL-1b and IL-18, as well as pyroptosis an inflammatory form of cell death. NLRP1 is maintained in an inactive state by the serine protease, DPP9. Whilst inhibition of DPP9 activates the NLRP1 inflammasome; however, these findings have been established in vitro using mouse and human cell lines. How DPP9 impacts NLRP1 inflammasome regulation in vivo has not yet been demonstrated.
Here we have identified patients displaying immune-associated manifestations, skin pigmentation abnormalities and neurological deficits that harbor loss-of-function mutations in DPP9. Patient keratinocytes display spontaneous activation of the NLRP1 inflammasome. We employed a mouse model harbouring a mutation in DPP9 that renders the protein catalytically inactive (Dpp9S759A/S759A) to model this condition. Dpp9S729A/S729A mice die within one day of birth through an unknown mechanism. Excitingly we have found that crossing Dpp9S759A/S759A mice to NLRP1 knockout mice (Nlrp1-/-) rescues neonate lethality. Dpp9S759A/S759A Nlrp1-/- mice appeared runted but are outwardly healthy and prove fertile. This dramatic amelioration of phenotype suggests that a major homeostatic role of DPP9 is to prevent NLRP1 inflammasome assembly. Additionally, we show that the Dpp9S759A/S759A neonate lethality can also be rescued by deletion of downstream components of the NLRP1 inflammasome, including ASC, GSDMD and IL-1R, with the phenotype of the rescued mice mirroring that of the Dpp9S759A/S759A Nlrp1-/- mice. In contrast, IL-18 deletion does not rescue Dpp9S759A/S759A lethality. Overall, we have shown the importance of DPP9 restraint of the NLRP1 inflammasome activation in vivo, with DPP9 deficiency resulting in NLRP1 driven inflammatory disease in both humans and mice.