Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection
Figure 7
Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates IL-1β and hypersensitivity to bacterial superinfection.
Step 1 –Phagocytes internalize Plasmodium DNA bound to hemozoin that activates TLR9 and the adaptor molecule named MyD88. Step 2 – MyD88 signaling triggers the expression of IL-12, which will initiate the production of IFN-γ by T lymphocytes and NK cells. Step 3 – Low levels of caspase-1-independent IL-1β induced by malaria infection. Step 4 – IFN-γ priming and MyD88 signaling in phagocytes will lead to enhanced expression of pro-caspase-1. K+ efflux as well as rupture (by hemozoin crystals) and release of lysosome contents will induce the assembly of ASC, NLRP3 and NLR12 inflammasomes and promote cleavage of pro-caspase-1. Step 5 - Bacterial superinfection triggers expression of high pro-IL-1β levels, in a TNF-α-dependent manner. Pro-IL-1β will be cleaved by active caspase-1 generated on step 4. Upon secondary bacterial infection, the malaria-primed macrophages will release deleterious amounts of IL-1β.