TLR4: the fall guy in sepsis?
Authors:Joseph Menassa1, Christina Nedeva1, Corey Pollock1 and Hamsa Puthalakath1
1 Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Vic 3086, Australia.
Keywords:
TLR4, TREML4, sepsis, Inflammation, apoptosis.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interests.
Please cite this article as:
Joseph Menassa, Christina Nedeva, Corey Pollock and Hamsa Puthalakath (2020). TLR4: the fall guy in sepsis? Cell Stress 4(12): 270-272. doi: 10.15698/cst2020.12.237
© 2020 Menassa et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
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.