TLR4: the fall guy in sepsis?

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.

Inflammation and Cell Death of the Innate and Adaptive Immune System during Sepsis

“…These limitations are evidenced by the multiple drug trials that have failed in the past, and in some instances increased mortality, largely due to efforts to target inflammation [19]. It is now known that a surge in inflammatory molecules signaling the critical "kick-start" to the immune system is necessary to fight invading pathogens, especially during culturable sepsis [4,20]. Therefore, targeting inflammation could be detrimental rather than beneficial.…”

Fractalkine deficiency attenuates LPS-induced acute kidney injury and podocyte apoptosis by targeting the PI3K/Akt signal pathway

“…The imbalance of body's immune function caused by apoptosis progression dysregulation is key factor inducing the immunosuppression of sepsis patients [21,22]. Apoptosis is a carefully regulated cell death process and mediated by multiple genes.…”

Fractalkine Deficiency Attenuates LPS-Induced Acute Kidney Injury and Podocytes Apoptosis by Targeting PI3K/Akt Signal Pathway

“…The imbalance of body's immune function caused by apoptosis progression dysregulation is key factor inducing the immunosuppression of sepsis patients [21,22]. Apoptosis is a carefully regulated cell death process and mediated by multiple genes.…”