NLRP12-expressing dendritic cells mediate both dissemination of infection and adaptive immune responses in visceral leishmaniasis

The NLR protein NLRP12 contributes to innate immunity, but the mechanism re-mains elusive. Infection of Nlrp12(-/-) or wild-type mice with Leishmania infantum led to aberrant parasite tropism. Parasites replicated to higher levels in livers of Nlrp12(-/-) mice than in the livers of WT mice and failed to disseminate to spleens. Most retained liver parasites resided in dendritic cells (DCs), with correspond-ingly fewer infected DCs in spleens. Furthermore, Nlrp12(-/-) DCs expressed lower CCR7 than WT DCs, failed to migrate toward CCL19 or CCL21 in chemo-taxis assays, and migrated poorly to draining lymph nodes after sterile inflamma-tion. Leishmania-infected Nlpr12(-/-) DCs were significantly less effective at trans-porting parasites to lymph nodes than WT DCs. Consistently, adaptive immune responses were also impaired in infected Nlrp12(-/-) mice. We hypothesize that Nlrp12-expressing DCs are required for efficient dissemination and immune clearance of L. infantum from the site of initial infection. This is at least partly due to the defective expression of CCR7.

Automated summary

The NLR protein NLRP12 is important for innate immunity, but its mechanism is still not fully understood. In this study, mice lacking Nlrp12 showed higher levels of parasite replication in the liver after infection with Leishmania infantum compared to wild-type mice, and the parasites failed to disseminate to the spleen. Most of the parasites in the liver were found in dendritic cells (DCs), while the number of infected DCs in the spleen was reduced. Furthermore, Nlrp12(-/-) DCs showed lower expression of CCR7, failed to migrate towards CCL19 or CCL21 in chemotaxis assays, and migrated poorly to draining lymph nodes after sterile inflammation. Leishmania-infected Nlpr12(-/-) DCs were also less effective at transporting parasites to lymph nodes compared to wild-type DCs. These findings suggest that Nlrp12-expressing DCs are necessary for efficient dissemination and immune clearance of L. infantum from the site of initial infection, partly due to defective CCR7 expression.