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DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages

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Abstract
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.

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Chicago
Moraes de Vasconcelos, Nathalia, Gwendolyn Vliegen, Amanda Gonçalves, Emilie De Hert, Rosa Martín-Pérez, Nina Van Opdenbosch, Anvesh Jallapally, et al. 2019. “DPP8/DPP9 Inhibition Elicits Canonical Nlrp1b Inflammasome Hallmarks in Murine Macrophages.” Life Science Alliance 2 (1).
APA
Moraes de Vasconcelos, N., Vliegen, G., Gonçalves, A., De Hert, E., Martín-Pérez, R., Van Opdenbosch, N., Jallapally, A., et al. (2019). DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages. LIFE SCIENCE ALLIANCE, 2(1).
Vancouver
1.
Moraes de Vasconcelos N, Vliegen G, Gonçalves A, De Hert E, Martín-Pérez R, Van Opdenbosch N, et al. DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages. LIFE SCIENCE ALLIANCE. 2019;2(1).
MLA
Moraes de Vasconcelos, Nathalia et al. “DPP8/DPP9 Inhibition Elicits Canonical Nlrp1b Inflammasome Hallmarks in Murine Macrophages.” LIFE SCIENCE ALLIANCE 2.1 (2019): n. pag. Print.
@article{8600762,
  abstract     = {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-1\ensuremath{\beta} 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-1\ensuremath{\beta} 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.},
  articleno    = {e201900313},
  author       = {Moraes de Vasconcelos, Nathalia and Vliegen, Gwendolyn and Gon\c{c}alves, Amanda and De Hert, Emilie and Mart{\'i}n-P{\'e}rez, Rosa and Van Opdenbosch, Nina and Jallapally, Anvesh and Geiss-Friedlander, Ruth and Lambeir, Anne-Marie and Augustyns, Koen and Van Der Veken, Pieter and De Meester, Ingrid and Lamkanfi, Mohamed},
  issn         = {2575-1077},
  journal      = {LIFE SCIENCE ALLIANCE},
  language     = {eng},
  number       = {1},
  pages        = {14},
  title        = {DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages},
  url          = {http://dx.doi.org/10.26508/lsa.201900313},
  volume       = {2},
  year         = {2019},
}

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