TY - JOUR T1 - DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900313 VL - 2 IS - 1 SP - e201900313 AU - Nathalia M de Vasconcelos AU - Gwendolyn Vliegen AU - Amanda Gonçalves AU - Emilie De Hert AU - Rosa Martín-Pérez AU - Nina Van Opdenbosch AU - Anvesh Jallapally AU - Ruth Geiss-Friedlander AU - Anne-Marie Lambeir AU - Koen Augustyns AU - Pieter Van Der Veken AU - Ingrid De Meester AU - Mohamed Lamkanfi Y1 - 2019/02/01 UR - https://www.life-science-alliance.org/content/2/1/e201900313.abstract N2 - Activating germline mutations in the human inflammasome sensor NLRP1 causes palmoplantar dyskeratosis and susceptibility to Mendelian autoinflammatory diseases. Recent studies have shown that the cytosolic serine dipeptidyl peptidases DPP8 and DPP9 suppress inflammasome activation upstream of NLRP1 and CARD8 in human keratinocytes and peripheral blood mononuclear cells. Moreover, pharmacological inhibition of DPP8/DPP9 protease activity was shown to induce pyroptosis in murine C57BL/6 macrophages without eliciting other inflammasome hallmark responses. Here, we show that DPP8/DPP9 inhibition in macrophages that express a Bacillus anthracis lethal toxin (LeTx)–sensitive Nlrp1b allele triggered significantly accelerated pyroptosis concomitant with caspase-1 maturation, ASC speck assembly, and secretion of mature IL-1β and IL-18. Genetic ablation of ASC prevented DPP8/DPP9 inhibition-induced caspase-1 maturation and partially hampered pyroptosis and inflammasome-dependent cytokine release, whereas deletion of caspase-1 or gasdermin D triggered apoptosis in the absence of IL-1β and IL-18 secretion. In conclusion, blockade of DPP8/DPP9 protease activity triggers rapid pyroptosis and canonical inflammasome hallmarks in primary macrophages that express a LeTx-responsive Nlrp1b allele. ER -