Pro-inflammatory mechanisms in sepsis.

Abstract

Sepsis is characterised by a hyper-inflammatory response due to microbial infection. We here review our current understanding of host mechanisms employed to mediate this hyper-inflammatory response, drawing together current knowledge pertaining to pathogen recognition and host pro-inflammatory response. Recognition of microbial derived ligands by pattern recognition receptors (PRRs) is a key step in initiating pro-inflammatory signalling pathways. Examples of PRRs linked to the aetiology of sepsis include Toll-like, C-type lectin, RIG-1-like and also Nod-like receptors, which are involved in the formation of the inflammasome, crucial for the maturation of some pro-inflammatory cytokines. Bacterial superantigens have evolved to exploit host MHC class II and T cell receptors (normally considered part of the adaptive immune response) as innate PRRs to propagate a so-called 'cytokine storm', while synergy between different microbial ligands and host-derived alarmins can augment the inflammatory response still further through as yet poorly understood interactions. The host pro-inflammatory response results in the characteristic features of inflammation: rubor, calor, dolor, and tumor. We will review herein the key mediators of inflammation in sepsis, identifying their overlapping and intersecting roles in vascular changes in tone, endothelial permeability, coagulation and contact activation, leukocyte mobilisation and activation.