Immunopathophysiology of human sepsis

Abstract

Sepsis is an ill-defined syndrome yet is a leading cause of morbidity and mortality worldwide. The most recent consensus defines sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, this definition belies the complexity and breadth of immune mechanisms involved in sepsis, which are characterized by simultaneous hyperinflammation and immune suppression. In this review, we describe the immunopathogenesis of sepsis and highlight some recent pathophysiological findings that have expanded our understanding of sepsis. Sepsis endotypes can be used to divide sepsis patients in different groups with distinct immune profiles and outcomes. We also summarize evidence on the role of the gut microbiome in sepsis immunity. The challenge of the coming years will be to translate our increasing knowledge about the molecular mechanisms underlying sepsis into therapies that improve relevant patient outcomes.

Keywords: Hyperinflammation; Immune suppression; Pathogenesis; Sepsis.

Fig. 1

Sepsis immunity and therapeutic targets. Sepsis is characterized by the simultaneous interplay of pro- and anti-inflammatory mechanisms. The magnitude of the immune response in sepsis depends on pathogen and host related factors. The proinflammatory response is characterized by among others the release of pro-inflammatory mediators, activation of the complement and the coagulation systems and the release of alarmins by necrotic cell death. Excessive inflammation can cause collateral damage to healthy tissue. The anti-inflammatory response is characterized by impaired immune cell function due to effector cell apoptosis, T cell exhaustion, reduced monocyte HLA-DR expression, increased expression of suppressor cells and inhibition of pro-inflammatory gene transcription. Anti-inflammatory changes may relate to epigenetic changes, in particular histone modifications and alterations in DNA methylation. Histones determine the accessibility of DNA to transcription factors; histone function can be modified by acetylation (Ac), methylation (Me), and phosphorylation (Ph) of their tails. DNA methylation happens at cytosine-guanine dinucleotides (denoted by C and G). The yellow boxes indicate a selection of therapeutic targets that have been clinically evaluated as interventions in the septic immune response. Abbreviations: TLR4: Toll-like receptor-4; TNF: tumour necrosis factor; PD-1: programmed cell death protein; IL-1RA: interleukin-1 receptor antagonist; IFN: interferon; G(M)-CSF: Granulocyte macrophage-colony stimulating factor.

Fig. 2

Immunometabolism in sepsis. Overview of key cellular energy pathways in innate immune cells in resting state (homeostasis), during acute inflammation and during prolonged critical illness. Arrows indicate upregulation (predominant role) or downregulation.

Fig. 3

Deriving biological meaning from multi-omics analysis in sepsis. The complexity of the septic response is being unravelled following the progress in the major -omics fields of genomics, epigenomics, transcriptomics, metabolomics, proteomics, lipidomics and microbiomics. The next challenge will be to fully integrate these multi-omics approaches in order to derive biologically meaningful insights which will lead to novel clinical applications that will be of value for the patient with sepsis.