TLR4: the fall guy in sepsis?
Sepsis and its impact on human health can be traced back to 1000 BC and continues to be a major health burden today. It causes about 11 million deaths world-wide of which, more than a third are due to neonatal sepsis. There is no effective treatment other than fluid resuscitation therapy and antibio...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Shared Science Publishers OG
2020-11-01
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| Series: | Cell Stress |
| Subjects: | |
| Online Access: | http://www.cell-stress.com/researcharticles/2020a-menassa-cell-stress/ |
| _version_ | 1819075752467890176 |
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| author | Joseph Menassa Christina Nedeva Corey Pollock Hamsa Puthalakath |
| author_facet | Joseph Menassa Christina Nedeva Corey Pollock Hamsa Puthalakath |
| author_sort | Joseph Menassa |
| collection | DOAJ |
| description | Sepsis and its impact on human health can be traced back to 1000 BC and continues to be a major health burden today. It causes about 11 million deaths world-wide of which, more than a third are due to neonatal sepsis. There is no effective treatment other than fluid resuscitation therapy and antibiotic treatment that leave patients immunosuppressed and vulnerable to nosocomial infections. Added to that, ageing population and the emergence of antibiotic resistant bacteria pose new challenges. Most of the deleterious effects of sepsis are due to the host response to the systemic infection. In the initial phase of infection, hyper activation of the immune system leads to cytokine storm, which could lead to organ failure and this accounts for about 15% of overall deaths. However, the subsequent immune paralysis phase (mostly attributed to apoptotic death of immune cells) accounts for about 85% of all deaths. Past clinical trials (more than 100 in the last 30 years) all targeted the inflammatory phase with little success, predictably, for inflammation is a necessary process to fight infection. In order to identify the regulators of immune cell death during sepsis, we carried out an unbiased, whole genome CRISPR screening in mice and identified Trigger Receptor Expressed in Myeloid-like 4 (Treml4) as the receptor that controls both the inflammatory phase and the immune suppression phase in sepsis (Nedeva et al. (2020) Nature Immunol, doi: 10.1038/s41590-020-0789-z). Characterising the Treml4 gene knockout mice revealed new insights into the relative roles of TLR4 and TREML4 in inducing the inflammatory cytokine storm during sepsis. |
| first_indexed | 2024-12-21T18:30:24Z |
| format | Article |
| id | doaj.art-2f049d1f16024aad8edbb64f93536f85 |
| institution | Directory Open Access Journal |
| issn | 2523-0204 |
| language | English |
| last_indexed | 2024-12-21T18:30:24Z |
| publishDate | 2020-11-01 |
| publisher | Shared Science Publishers OG |
| record_format | Article |
| series | Cell Stress |
| spelling | doaj.art-2f049d1f16024aad8edbb64f93536f852022-12-21T18:54:17ZengShared Science Publishers OGCell Stress2523-02042020-11-0141227027210.15698/cst2020.12.237TLR4: the fall guy in sepsis?Joseph Menassa0Christina Nedeva1Corey Pollock2Hamsa Puthalakath3Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Vic 3086, Australia.Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Vic 3086, Australia.Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Vic 3086, Australia.Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Vic 3086, Australia.Sepsis and its impact on human health can be traced back to 1000 BC and continues to be a major health burden today. It causes about 11 million deaths world-wide of which, more than a third are due to neonatal sepsis. There is no effective treatment other than fluid resuscitation therapy and antibiotic treatment that leave patients immunosuppressed and vulnerable to nosocomial infections. Added to that, ageing population and the emergence of antibiotic resistant bacteria pose new challenges. Most of the deleterious effects of sepsis are due to the host response to the systemic infection. In the initial phase of infection, hyper activation of the immune system leads to cytokine storm, which could lead to organ failure and this accounts for about 15% of overall deaths. However, the subsequent immune paralysis phase (mostly attributed to apoptotic death of immune cells) accounts for about 85% of all deaths. Past clinical trials (more than 100 in the last 30 years) all targeted the inflammatory phase with little success, predictably, for inflammation is a necessary process to fight infection. In order to identify the regulators of immune cell death during sepsis, we carried out an unbiased, whole genome CRISPR screening in mice and identified Trigger Receptor Expressed in Myeloid-like 4 (Treml4) as the receptor that controls both the inflammatory phase and the immune suppression phase in sepsis (Nedeva et al. (2020) Nature Immunol, doi: 10.1038/s41590-020-0789-z). Characterising the Treml4 gene knockout mice revealed new insights into the relative roles of TLR4 and TREML4 in inducing the inflammatory cytokine storm during sepsis.http://www.cell-stress.com/researcharticles/2020a-menassa-cell-stress/tlr4treml4sepsisinflammationapoptosis |
| spellingShingle | Joseph Menassa Christina Nedeva Corey Pollock Hamsa Puthalakath TLR4: the fall guy in sepsis? Cell Stress tlr4 treml4 sepsis inflammation apoptosis |
| title | TLR4: the fall guy in sepsis? |
| title_full | TLR4: the fall guy in sepsis? |
| title_fullStr | TLR4: the fall guy in sepsis? |
| title_full_unstemmed | TLR4: the fall guy in sepsis? |
| title_short | TLR4: the fall guy in sepsis? |
| title_sort | tlr4 the fall guy in sepsis |
| topic | tlr4 treml4 sepsis inflammation apoptosis |
| url | http://www.cell-stress.com/researcharticles/2020a-menassa-cell-stress/ |
| work_keys_str_mv | AT josephmenassa tlr4thefallguyinsepsis AT christinanedeva tlr4thefallguyinsepsis AT coreypollock tlr4thefallguyinsepsis AT hamsaputhalakath tlr4thefallguyinsepsis |