2. Academic Validation
  3. DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages

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

  • Life Sci Alliance. 2019 Feb 4;2(1):e201900313. doi: 10.26508/lsa.201900313.
Nathalia M de Vasconcelos 1 2,  Gwendolyn Vliegen 3,  Amanda Gonçalves 2 4 5,  Emilie De Hert 3,  Rosa Martín-Pérez 6,  Nina Van Opdenbosch 1 2 6,  Anvesh Jallapally 7,  Ruth Geiss-Friedlander 8,  Anne-Marie Lambeir 3,  Koen Augustyns 7,  Pieter Van Der Veken 7,  Ingrid De Meester 3,  Mohamed Lamkanfi 9 2 6
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Ghent University, Ghent, Belgium.
  • 2 VIB-UGhent Center for Inflammation Research, VIB, Ghent, Belgium.
  • 3 Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
  • 4 VIB Bioimaging Core, VIB, Ghent, Belgium.
  • 5 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 6 Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.
  • 7 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
  • 8 Institut für Molekularbiologie, Universitätsmedizin Göttingen, Göttingen, Germany.
  • 9 Department of Internal Medicine, Ghent University, Ghent, Belgium [email protected].
PMID: 30718379 DOI: 10.26508/lsa.201900313
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.

Figures