RT Journal Article SR Electronic T1 DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900313 DO 10.26508/lsa.201900313 VO 2 IS 1 A1 Nathalia M de Vasconcelos A1 Gwendolyn Vliegen A1 Amanda Gonçalves A1 Emilie De Hert A1 Rosa Martín-Pérez A1 Nina Van Opdenbosch A1 Anvesh Jallapally A1 Ruth Geiss-Friedlander A1 Anne-Marie Lambeir A1 Koen Augustyns A1 Pieter Van Der Veken A1 Ingrid De Meester A1 Mohamed Lamkanfi YR 2019 UL https://www.life-science-alliance.org/content/2/1/e201900313.abstract AB 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.