Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretion
Abstract 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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05476-3 |
| _version_ | 1811302163587006464 |
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| author | Laura Migliari Branco Marcelo Pires Amaral Henning Boekhoff Ana Beatriz Figueiredo de Lima Ingrid Sancho Farias Silvia Lucena Lage Gustavo José Silva Pereira Bernardo Simões Franklin Karina Ramalho Bortoluci |
| author_facet | Laura Migliari Branco Marcelo Pires Amaral Henning Boekhoff Ana Beatriz Figueiredo de Lima Ingrid Sancho Farias Silvia Lucena Lage Gustavo José Silva Pereira Bernardo Simões Franklin Karina Ramalho Bortoluci |
| author_sort | Laura Migliari Branco |
| collection | DOAJ |
| description | Abstract 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-κB-mediated priming of pro-IL-1β, thus suggesting these proteases act downstream of the NAIP/NLRC4 inflammasome activation. IL-1β 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-1β secretion was abrogated in the absence of both GSDMD and cathepsins, demonstrating their non-redundant roles for the optimal IL-1β 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. |
| first_indexed | 2024-04-13T07:23:08Z |
| format | Article |
| id | doaj.art-0d5a4821332f4b70a59baaf70c4b95da |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T07:23:08Z |
| publishDate | 2022-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-0d5a4821332f4b70a59baaf70c4b95da2022-12-22T02:56:33ZengNature Publishing GroupCell Death and Disease2041-48892022-12-01131211010.1038/s41419-022-05476-3Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretionLaura Migliari Branco0Marcelo Pires Amaral1Henning Boekhoff2Ana Beatriz Figueiredo de Lima3Ingrid Sancho Farias4Silvia Lucena Lage5Gustavo José Silva Pereira6Bernardo Simões Franklin7Karina Ramalho Bortoluci8Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)National Institute of Allergy and Infectious Diseases, National Institute of HealthDepartamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)Institute of Innate Immunity, University HospitalsDepartamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)Abstract 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-κB-mediated priming of pro-IL-1β, thus suggesting these proteases act downstream of the NAIP/NLRC4 inflammasome activation. IL-1β 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-1β secretion was abrogated in the absence of both GSDMD and cathepsins, demonstrating their non-redundant roles for the optimal IL-1β 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.https://doi.org/10.1038/s41419-022-05476-3 |
| spellingShingle | Laura Migliari Branco Marcelo Pires Amaral Henning Boekhoff Ana Beatriz Figueiredo de Lima Ingrid Sancho Farias Silvia Lucena Lage Gustavo José Silva Pereira Bernardo Simões Franklin Karina Ramalho Bortoluci Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretion Cell Death and Disease |
| title | Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretion |
| title_full | Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretion |
| title_fullStr | Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretion |
| title_full_unstemmed | Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretion |
| title_short | Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1β secretion |
| title_sort | lysosomal cathepsins act in concert with gasdermin d during naip nlrc4 dependent il 1β secretion |
| url | https://doi.org/10.1038/s41419-022-05476-3 |
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