CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex.
LPS-activated neutrophils secrete IL-1β by activation of TLR-4. Based on studies in macrophages, it is likely that ROS and lysosomal destabilization regulated by Syk activation may also be involved. Since neutrophils have abundant expression of the ITIM-containing co-receptor CEACAM1 and Gram-negati...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3320586?pdf=render |
| _version_ | 1818440860831842304 |
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| author | Rongze Lu Hao Pan John E Shively |
| author_facet | Rongze Lu Hao Pan John E Shively |
| author_sort | Rongze Lu |
| collection | DOAJ |
| description | LPS-activated neutrophils secrete IL-1β by activation of TLR-4. Based on studies in macrophages, it is likely that ROS and lysosomal destabilization regulated by Syk activation may also be involved. Since neutrophils have abundant expression of the ITIM-containing co-receptor CEACAM1 and Gram-negative bacteria such as Neisseria utilize CEACAM1 as a receptor that inhibits inflammation, we hypothesized that the overall production of IL-1β in LPS treated neutrophils may be negatively regulated by CEACAM1. We found that LPS treated neutrophils induced phosphorylation of Syk resulting in the formation of a complex including TLR4, p-Syk, and p-CEACAM1, which in turn, recruited the inhibitory phosphatase SHP-1. LPS treatment leads to ROS production, lysosomal damage, caspase-1 activation and IL-1β secretion in neutrophils. The absence of this regulation in Ceacam1⁻/⁻ neutrophils led to hyper production of IL-1β in response to LPS. The hyper production of IL-1β was abrogated by in vivo reconstitution of wild type but not ITIM-mutated CEACAM1 bone marrow stem cells. Blocking Syk activation by kinase inhibitors or RNAi reduced Syk phosphorylation, lysosomal destabilization, ROS production, and caspase-1 activation in Ceacam1⁻/⁻ neutrophils. We conclude that LPS treatment of neutrophils triggers formation of a complex of TLR4 with pSyk and pCEACAM1, which upon recruitment of SHP-1 to the ITIMs of pCEACAM1, inhibits IL-1β production by the inflammasome. Thus, CEACAM1 fine-tunes IL-1β production in LPS treated neutrophils, explaining why the additional utilization of CEACAM1 as a pathogen receptor would further inhibit inflammation. |
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| id | doaj.art-ef3d6ea10f64436b972fdbb9ab0fad94 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-14T18:19:04Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj.art-ef3d6ea10f64436b972fdbb9ab0fad942022-12-21T22:52:07ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742012-01-0184e100259710.1371/journal.ppat.1002597CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex.Rongze LuHao PanJohn E ShivelyLPS-activated neutrophils secrete IL-1β by activation of TLR-4. Based on studies in macrophages, it is likely that ROS and lysosomal destabilization regulated by Syk activation may also be involved. Since neutrophils have abundant expression of the ITIM-containing co-receptor CEACAM1 and Gram-negative bacteria such as Neisseria utilize CEACAM1 as a receptor that inhibits inflammation, we hypothesized that the overall production of IL-1β in LPS treated neutrophils may be negatively regulated by CEACAM1. We found that LPS treated neutrophils induced phosphorylation of Syk resulting in the formation of a complex including TLR4, p-Syk, and p-CEACAM1, which in turn, recruited the inhibitory phosphatase SHP-1. LPS treatment leads to ROS production, lysosomal damage, caspase-1 activation and IL-1β secretion in neutrophils. The absence of this regulation in Ceacam1⁻/⁻ neutrophils led to hyper production of IL-1β in response to LPS. The hyper production of IL-1β was abrogated by in vivo reconstitution of wild type but not ITIM-mutated CEACAM1 bone marrow stem cells. Blocking Syk activation by kinase inhibitors or RNAi reduced Syk phosphorylation, lysosomal destabilization, ROS production, and caspase-1 activation in Ceacam1⁻/⁻ neutrophils. We conclude that LPS treatment of neutrophils triggers formation of a complex of TLR4 with pSyk and pCEACAM1, which upon recruitment of SHP-1 to the ITIMs of pCEACAM1, inhibits IL-1β production by the inflammasome. Thus, CEACAM1 fine-tunes IL-1β production in LPS treated neutrophils, explaining why the additional utilization of CEACAM1 as a pathogen receptor would further inhibit inflammation.http://europepmc.org/articles/PMC3320586?pdf=render |
| spellingShingle | Rongze Lu Hao Pan John E Shively CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. PLoS Pathogens |
| title | CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. |
| title_full | CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. |
| title_fullStr | CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. |
| title_full_unstemmed | CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. |
| title_short | CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. |
| title_sort | ceacam1 negatively regulates il 1β production in lps activated neutrophils by recruiting shp 1 to a syk tlr4 ceacam1 complex |
| url | http://europepmc.org/articles/PMC3320586?pdf=render |
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