Gram-negative bacterial sepsis is characterized by increased inflammation and tissue injury, mediated by a rise in pro-inflammatory cytokines. Elderly and immunocompromised patients are at increased risk of death from this condition, whilst current therapies are less efficient in these groups of individuals. MD2-toll-like receptor 4 (TLR-4) induces inflammatory cytokines via the activation of the immune system by bacterial endotoxin lipopolysaccharide (LPS) of Gram-negative bacteria, causing sepsis. Therefore, initial studies were focused on TLR4 as the target for treating sepsis. However, inhibition of TLRs will have lethal effects in immunocompromised patients. Thus, novel approaches aim to inhibit the hyperinflammation that follows the bacterial infection.
In this study, a natural oligosaccharide that has previously demonstrated TLR4-modulating activity, was investigated to derive a product that can modulate both pro- and anti-inflammatory cytokines. Low-molecular weight chitosans, such as chitohexaose, induce macrophages to an anti-inflammatory phenotype. This is mediated by the secretion of IL-10, via the non-canonical TLR4 signalling pathway. Meanwhile, chitohexaose inhibits the release of inflammatory factors initiated by TNF-α and IL-6.
The effect of AVR-25, a modified form of chitohexaose (from Carbosynth - OH07433), has been tested in a murine model of bacterial peritonitis, known as the cecal ligation and puncture (CLP) model. Administration of AVR-25 following CLP, alone or in combination with standard antibiotic imipenem (in combination with cilastatin from Carbosynth - FC20432), resulted in reduced mortality and organ injury in both young and aged mice. It has been demonstrated that AVR-25 selectively binds to TLR4 (IC50 = 0.15 μM), which leads to activation of M2 macrophages and release of anti-inflammatory cytokine IL-10.
For further information, please refer to the original paper: Das et al, 2019.