Host innate immune responses to sepsis

Abstract

The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both pro-inflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so-called pathogen-associated molecular patterns or derived from the host, so-called danger-associated molecular patterns. Further dissection of the role of host-pathogen interactions, the cytokine response, the coagulation cascade, and their multidirectional interactions in sepsis should lead toward the development of new therapeutic strategies in sepsis.

Keywords: activated protein C; coagulation; danger-associated molecular patterns (DAMP); innate immunity; myeloid related protein (Mrp)-8/14; neutrophil extracellular traps (NET); pathogen-associated molecular patterns (PAMP); pattern recognition receptors; protease activated receptors; sepsis.

Figure 1. The host response to sepsis. The host response to sepsis is characterized by both pro-inflammatory responses and anti-inflammatory immune suppressive responses. Inflammatory responses are initiated by interaction between pathogen-associated molecular patterns (PAMPs) expressed by pathogens or endogenous danger signals (danger-associated molecular patterns, DAMPs) and pattern recognition receptors (PRR) expressed by host immune cells. Exaggerated inflammation with collateral tissue damage and necrotic cell death will result in the release of DAMPs that can perpetuate ongoing inflammation. The pro-inflammatory response is enhanced by activation of leukocytes, complement, and the coagulation system. The anti-inflammatory immune suppressive response depends on impaired function of immune cells, neuroendocrine regulation, and inhibition of pro-inflammatory gene transcription. Importantly, direction, extent, and duration of the septic response is determined by both host factors, such as genetic composition, age, comorbidity, and medication, and pathogen factors, including microbial load and virulence. LPS, lipopolysaccharide; LTA, lipoteichoic acid; HSP, heat shock protein; HMGB-1, high mobility group box-1 protein; IL, interleukin; IL-1RA, IL-1 receptor antagonist; MRP8/14, migration inhibitory factor-related protein-8/14; NETs, neutrophils extracellular traps; T, T lymphocytes; B, B lymphocytes; DC, dendritic cells; Tregs, regulatory T lymphocytes; TLR, toll-like receptor.