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The immunopathology of sepsis and potential therapeutic targets

Nature Reviews Immunology volume 17, pages 407–420 (2017)Cite this article

Subjects

Key Points

  • Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection.

  • The sepsis-associated host response is characterized by concurrent excessive inflammatory, catabolic, metabolic and immune-suppressive features, and a failure to return to homeostasis, which often results in a condition referred to as chronic critical illness and is not fundamentally different from the sustained host response aberrations that are induced by severe non-infectious injuries.

  • Sepsis is a very heterogeneous syndrome, and current knowledge does not enable the stratification of patients into more homogeneous subgroups in which specific and potentially targetable host response derailments drive pathology.

  • Key pro-inflammatory responses during sepsis include the activation of the complement system, the coagulation system, the vascular endothelium, neutrophils and platelets, whereas immune suppression is primarily caused by the reprogramming of antigen-presenting cells, and the apoptosis and exhaustion of lymphocytes.

  • Individuals who survive sepsis frequently suffer from long-term cognitive and physical impairments, the aetiology of which is uncertain.

  • Strategies to modulate the aberrant host response have been unsuccessful in a large number of clinical trials, which may at least in part be related to the inadequate selection of therapeutic targets and an inability to select the patients who might benefit from a certain intervention.

  • Future research should focus the discovery and validation of biomarkers that reflect the predominant pathophysiological mechanisms at different body sites, and that can guide the selection of patients for targeted therapies and the monitoring thereof.

Abstract

Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.

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Figure 1: The host response to infection and during sepsis.
Figure 2: Activation of the coagulation and complement systems during sepsis.
Figure 3: Metabolic and epigenetic pathways lead to an imbalance of immune responses in sepsis.
Figure 4: Genomic responses of leukocytes in sepsis.
Figure 5: The development of therapeutic drugs for sepsis.

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Acknowledgements

This work was supported by a TOP subsidy from the Netherlands Organization for Scientific Research (to T.v.d.P. and M.G.N.). M.G.N. was partly supported by a European Research Council Consolidator Grant (3310372) and a Spinoza grant from the Netherlands Organization for Scientific Research.

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Authors and Affiliations

  1. Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands

    Tom van der Poll & Brendon P. Scicluna

  2. Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands

    Tom van der Poll

  3. Department of Internal Medicine, Radboud University Medical Center,

    Frank L. van de Veerdonk & Mihai G. Netea

  4. Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 8, Nijmegen, 6525 GA, The Netherlands

    Frank L. van de Veerdonk & Mihai G. Netea

  5. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands

    Brendon P. Scicluna

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Glossary

Homeostasis

A process by which biological systems maintain stability while adjusting to circumstances, which promotes survival.

Pathogen-associated molecular patterns

(PAMPs). Molecular motifs that are associated with classes of pathogens and are capable of ligating innate immune receptors known as pattern recognition receptors.

Pattern recognition receptors

(PRRs). Receptors that recognize molecules expressed by pathogens and host molecules released by injured cells: that is, pathogen-associated molecular patterns and damage-associated molecular patterns, respectively.

Damage-associated molecular patterns

(DAMPs). Host-derived molecules — such as uric acid, ATP and heat shock proteins — that are released from injured cells and can activate pattern recognition receptors.

Immunothrombosis

Thrombosis that is initiated by the innate immune system and that aims to provide a first line of defence to locally control an infection.

Protease-activated receptors

(PARs). A family of G protein-coupled receptors that can be specifically activated by coagulation proteases and various other serine proteases.

Histones

Intranuclear proteins that package and order the DNA into structural units called nucleosomes.

Glycocalyx

A complex network of cell-bound proteoglycans, glycosaminoglycan side chains and sialoproteins that lines the luminal side of endothelial cells.

Lymphocyte exhaustion

A term that is used to indicate the functional impairment of antigen-specific lymphocytes in the context of a persistently high antigen load.

Apoptosis

A common form of cell death that is also known as intrinsic or programmed cell death. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

Epigenetic regulation

Reversible biochemical changes to chromatin that influence gene expression but do not involve alterations in DNA sequence.

MicroRNAs

(miRNAs). Small single-stranded RNA molecules that function in the post-transcriptional regulation of gene expression.

Demethylase

An enzyme that induces demethylation: that is, the removal of a methyl group from a molecule.

Deacetylase

An enzyme that induces deacetylation: that is, the removal of an acetyl group from a molecule.

Trained immunity

Memory of the innate immune system that is mediated by monocytes, macrophages and natural killer cells, and manifests as protection against reinfection by the same or different pathogens in organisms that lack adaptive immune responses.

Warburg effect

The phenomenon in which inflammatory and cancer cells demonstrate a shift in energy metabolism away from oxidative phosphorylation (which is dominant in resting cells) towards aerobic glycolysis, thereby making them able to more rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins.

Mesenchymal stem cells

Multipotent cells that can be derived from a wide variety of tissues including bone marrow, adipose tissue, cord blood and muscles. The immuno- phenotype of these cells typically includes the expression of surface markers such as CD73, CD90 and CD105, and a lack of the haematopoietic markers CD45, CD34, CD14 and CD11.

Theranostics

Diagnostic testing used in combination with targeted therapeutics.

Superantigens

Antigens that induce nonspecific activation of T cells, which results in polyclonal T cell activation.

Immune checkpoints

Negative regulators of the immune system that are important for maintaining self-tolerance, preventing autoimmunity and protecting tissues from immune-mediated injury.

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van der Poll, T., van de Veerdonk, F., Scicluna, B. et al. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol 17, 407–420 (2017). https://doi.org/10.1038/nri.2017.36

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