Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases.
The intraerythrocytic parasite Plasmodium -- the causative agent of malaria -- produces an inorganic crystal called hemozoin (Hz) during the heme detoxification process, which is released into the circulation during erythrocyte lysis. Hz is rapidly ingested by phagocytes and induces the production o...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-08-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC2722371?pdf=render |
| _version_ | 1811226249741205504 |
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| author | Marina Tiemi Shio Stephanie C Eisenbarth Myriam Savaria Adrien F Vinet Marie-Josée Bellemare Kenneth W Harder Fayyaz S Sutterwala D Scott Bohle Albert Descoteaux Richard A Flavell Martin Olivier |
| author_facet | Marina Tiemi Shio Stephanie C Eisenbarth Myriam Savaria Adrien F Vinet Marie-Josée Bellemare Kenneth W Harder Fayyaz S Sutterwala D Scott Bohle Albert Descoteaux Richard A Flavell Martin Olivier |
| author_sort | Marina Tiemi Shio |
| collection | DOAJ |
| description | The intraerythrocytic parasite Plasmodium -- the causative agent of malaria -- produces an inorganic crystal called hemozoin (Hz) during the heme detoxification process, which is released into the circulation during erythrocyte lysis. Hz is rapidly ingested by phagocytes and induces the production of several pro-inflammatory mediators such as interleukin-1beta (IL-1beta). However, the mechanism regulating Hz recognition and IL-1beta maturation has not been identified. Here, we show that Hz induces IL-1beta production. Using knockout mice, we showed that Hz-induced IL-1beta and inflammation are dependent on NOD-like receptor containing pyrin domain 3 (NLRP3), ASC and caspase-1, but not NLRC4 (NLR containing CARD domain). Furthermore, the absence of NLRP3 or IL-1beta augmented survival to malaria caused by P. chabaudi adami DS. Although much has been discovered regarding the NLRP3 inflammasome induction, the mechanism whereby this intracellular multimolecular complex is activated remains unclear. We further demonstrate, using pharmacological and genetic intervention, that the tyrosine kinases Syk and Lyn play a critical role in activation of this inflammasome. These findings not only identify one way by which the immune system is alerted to malarial infection but also are one of the first to suggest a role for tyrosine kinase signaling pathways in regulation of the NLRP3 inflammasome. |
| first_indexed | 2024-04-12T09:21:51Z |
| format | Article |
| id | doaj.art-b98814ba35b5496b9d4c9d2461d8a623 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-12T09:21:51Z |
| publishDate | 2009-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-b98814ba35b5496b9d4c9d2461d8a6232022-12-22T03:38:37ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742009-08-0158e100055910.1371/journal.ppat.1000559Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases.Marina Tiemi ShioStephanie C EisenbarthMyriam SavariaAdrien F VinetMarie-Josée BellemareKenneth W HarderFayyaz S SutterwalaD Scott BohleAlbert DescoteauxRichard A FlavellMartin OlivierThe intraerythrocytic parasite Plasmodium -- the causative agent of malaria -- produces an inorganic crystal called hemozoin (Hz) during the heme detoxification process, which is released into the circulation during erythrocyte lysis. Hz is rapidly ingested by phagocytes and induces the production of several pro-inflammatory mediators such as interleukin-1beta (IL-1beta). However, the mechanism regulating Hz recognition and IL-1beta maturation has not been identified. Here, we show that Hz induces IL-1beta production. Using knockout mice, we showed that Hz-induced IL-1beta and inflammation are dependent on NOD-like receptor containing pyrin domain 3 (NLRP3), ASC and caspase-1, but not NLRC4 (NLR containing CARD domain). Furthermore, the absence of NLRP3 or IL-1beta augmented survival to malaria caused by P. chabaudi adami DS. Although much has been discovered regarding the NLRP3 inflammasome induction, the mechanism whereby this intracellular multimolecular complex is activated remains unclear. We further demonstrate, using pharmacological and genetic intervention, that the tyrosine kinases Syk and Lyn play a critical role in activation of this inflammasome. These findings not only identify one way by which the immune system is alerted to malarial infection but also are one of the first to suggest a role for tyrosine kinase signaling pathways in regulation of the NLRP3 inflammasome.http://europepmc.org/articles/PMC2722371?pdf=render |
| spellingShingle | Marina Tiemi Shio Stephanie C Eisenbarth Myriam Savaria Adrien F Vinet Marie-Josée Bellemare Kenneth W Harder Fayyaz S Sutterwala D Scott Bohle Albert Descoteaux Richard A Flavell Martin Olivier Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathogens |
| title | Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. |
| title_full | Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. |
| title_fullStr | Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. |
| title_full_unstemmed | Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. |
| title_short | Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. |
| title_sort | malarial hemozoin activates the nlrp3 inflammasome through lyn and syk kinases |
| url | http://europepmc.org/articles/PMC2722371?pdf=render |
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