Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death.
Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infe...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-10-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5063320?pdf=render |
| _version_ | 1818316623453356032 |
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| author | Naomi H Philip Alexandra DeLaney Lance W Peterson Melanie Santos-Marrero Jennifer T Grier Yan Sun Meghan A Wynosky-Dolfi Erin E Zwack Baofeng Hu Tayla M Olsen Anthony Rongvaux Scott D Pope Carolina B López Andrew Oberst Daniel P Beiting Jorge Henao-Mejia Igor E Brodsky |
| author_facet | Naomi H Philip Alexandra DeLaney Lance W Peterson Melanie Santos-Marrero Jennifer T Grier Yan Sun Meghan A Wynosky-Dolfi Erin E Zwack Baofeng Hu Tayla M Olsen Anthony Rongvaux Scott D Pope Carolina B López Andrew Oberst Daniel P Beiting Jorge Henao-Mejia Igor E Brodsky |
| author_sort | Naomi H Philip |
| collection | DOAJ |
| description | Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense. |
| first_indexed | 2024-12-13T09:24:22Z |
| format | Article |
| id | doaj.art-f64d18916f2d4f71922dc3bc9241243c |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-13T09:24:22Z |
| publishDate | 2016-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-f64d18916f2d4f71922dc3bc9241243c2022-12-21T23:52:39ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-10-011210e100591010.1371/journal.ppat.1005910Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death.Naomi H PhilipAlexandra DeLaneyLance W PetersonMelanie Santos-MarreroJennifer T GrierYan SunMeghan A Wynosky-DolfiErin E ZwackBaofeng HuTayla M OlsenAnthony RongvauxScott D PopeCarolina B LópezAndrew OberstDaniel P BeitingJorge Henao-MejiaIgor E BrodskyCaspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.http://europepmc.org/articles/PMC5063320?pdf=render |
| spellingShingle | Naomi H Philip Alexandra DeLaney Lance W Peterson Melanie Santos-Marrero Jennifer T Grier Yan Sun Meghan A Wynosky-Dolfi Erin E Zwack Baofeng Hu Tayla M Olsen Anthony Rongvaux Scott D Pope Carolina B López Andrew Oberst Daniel P Beiting Jorge Henao-Mejia Igor E Brodsky Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. PLoS Pathogens |
| title | Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. |
| title_full | Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. |
| title_fullStr | Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. |
| title_full_unstemmed | Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. |
| title_short | Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. |
| title_sort | activity of uncleaved caspase 8 controls anti bacterial immune defense and tlr induced cytokine production independent of cell death |
| url | http://europepmc.org/articles/PMC5063320?pdf=render |
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