期刊
CELL DEATH & DISEASE
卷 13, 期 12, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-022-05476-3
关键词
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类别
资金
- FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brazil)
- European Research Council [2017/21814-7, 2015/09029-7, 2018/19252-3, 2021/03371-6, SFBTRR57]
- German Research Foundation (DFG)
- Brazilian Research Council (CNPq) [2017/25942-0]
- [308896/2019-0]
- [402100/2016-6]
Recent studies have shown that the NAIP/NLRC4 inflammasome can be activated not only in bacterial infections but also in non-bacterial infections and sterile inflammation. The involvement of cathepsins, known for their role in NLRP3 activation, in the regulation of NAIP/NLRC4-mediated responses to cytosolic flagellin has also been discovered. This study provides new insights into the role of cathepsins in the NAIP/NLRC4 inflammasome activation.
The NAIP/NLRC4 inflammasome is classically associated with the detection of bacterial invasion to the cytosol. However, recent studies have demonstrated that NAIP/NLRC4 is also activated in non-bacterial infections, and in sterile inflammation. Moreover, in addition to the well-established model for the detection of bacterial proteins by NAIP proteins, the participation of other cytosolic pathways in the regulation of NAIP/NLRC4-mediated responses has been reported in distinct contexts. Using pharmacological inhibition and genetic deletion, we demonstrate here that cathepsins, well known for their involvement in NLRP3 activation, also regulate NAIP/NLRC4 responses to cytosolic flagellin in murine and human macrophages. In contrast to that observed for NLRP3 agonists, cathepsins inhibition did not reduce ASC speck formation or caspase-1 maturation in response to flagellin, ruling out their participation in the effector phase of NAIP/NLRC4 activation. Moreover, cathepsins had no impact on NF-kappa B-mediated priming of pro-IL-1 beta, thus suggesting these proteases act downstream of the NAIP/NLRC4 inflammasome activation. IL-1 beta levels secreted in response to flagellin were reduced in the absence of either cathepsins or Gasdermin-D (GSDMD), a molecule involved in the induction of pyroptosis and cytokines release. Notably, IL-1 beta secretion was abrogated in the absence of both GSDMD and cathepsins, demonstrating their non-redundant roles for the optimal IL-1 beta release in response to cytosolic flagellin. Given the central role of NAIP/NLRC4 inflammasomes in controlling infection and, also, induction of inflammatory pathologies, many efforts have been made to uncover novel molecules involved in their regulation. Thus, our findings bring together a relevant contribution by describing the role of cathepsins as players in the NAIP/NLRC4-mediated responses.
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