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Apoptosis and caspases regulate death and inflammation in sepsis

Key Points

  • Sepsis is the systemic inflammatory response that occurs following severe infections and is characterized by a range of features, which might include fever, hypotension, altered mental status and shortness of breath.

  • Although the predominant theory has been that the death of patients with sepsis was due to an over-exuberant inflammatory response, it is now apparent that many deaths are due to failure of the host to mount an effective immunological response. As the sepsis progresses, patients develop a state of immunoparalysis, marked by an inability of the host to eradicate the invading pathogen and predisposition to secondary infections.

  • A major cause of the immunoparalysis of sepsis is the loss of key immune effector cells, including dendritic cells and lymphocytes. These cells die owing to sepsis-induced apoptosis.

  • Uptake of apoptotic cells by professional scavenging cells induces a T helper 2 (TH2) phenotype or anergy in these phagocytic cells, thereby contributing to the immune suppression.

  • Blockade of sepsis-induced apoptosis by a number of methods, including overexpression of B-cell lymphoma 2 (BCL-2) or AKT results in improved survival. This finding suggests that apoptosis is an important process in the pathophysiology of the disorder.

  • It is now clear that caspases have other functions in the immune system in addition to their role as cell-death proteases. Caspases might also regulate inflammation, cellular activation and cellular proliferation.

  • Strategies to block sepsis-induced apoptosis might represent a novel therapy of this highly lethal disorder.

Abstract

Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells. Rectification of this apoptotic–inflammatory imbalance using modulators of caspases and other components of the cell-death pathway have shown striking efficacy in stringent animal models of sepsis, indicating an entirely novel path forward for the clinical treatment of human sepsis.

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Figure 1: Immune response and death in sepsis.
Figure 2: Sepsis-induced loss of immune effector cells.
Figure 3: Impact of apoptosis on immune function.
Figure 4: Cross-talk between the two pathways of apoptotic cell death.

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Acknowledgements

Work from the Hotchkiss laboratory was supported by grants from the US National Institutes of Health, and the Alan A. and Edith L. Wolff Foundation.

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Correspondence to Donald W. Nicholson.

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Glossary

Endotoxin

Endotoxin is the lipopolysaccharide component that constitutes the cell wall of Gram-negative bacteria. It is a potent activator of many cells including monocytes, macrophages and B cells. During sepsis induced by Gram-negative bacteria, endotoxin is released into the bloodstream thereby resulting in many of the clinical signs and symptoms of sepsis.

Apoptosis

Apoptosis involves cell shrinkage, chromatin condensation in the periphery of the nucleus, cell-membrane blebbing and DNA fragmentation into multiples of 180 base pairs. Eventually, the cell breaks up into many membrane-bound apoptotic bodies, which are phagocytosed by neighbouring cells.

Caspases

A family of cysteine proteinases that are involved in the initiation and effector stages of apoptosis.

Follicular dendritic cells

(FDCs). Cells with a dendritic morphology that are present in the B-cell areas of spleen and lymph nodes. FDCs have intact antigens on their surface that are held in immune complexes, and B cells present in the lymph node can interact with these antigen-presenting cells. FDCs are of non-haematopoietic origin and are not related to other types of dendritic cell.

Interdigitating dendritic cells

A potent antigen-presenting cell that is rich in MHC class II molecules. Interdigitating dendritic cells take up antigen in the periphery and migrate to the paracortical region of lymph nodes and spleen where they interact with T cells.

Septic shock

Sepsis is the host response that occurs owing to the presence of bacteria and/or their products within the bloodstream. Patients with a severe life-threatening form of sepsis in which there is evidence of inadequate organ perfusion (for example, shock, decreased renal function and depressed mental state) are stated to be in septic shock.

Lymphopaenia

A deficiency of lymphocytes in the blood circulation.

T helper 2 (TH2)-cell

The definition of a CD4+ T cell that has differentiated into a cell that produces the cytokines interleukin-4 (IL-4), IL-5 and IL-13.

Necrotic cells

Cells that are exposed to the high concentrations of purified perforin that are typically delivered by cytolytic cells, such as natural killer cells and cytotoxic T lymphocytes, and usually die by osmotic lysis, a form of necrotic death.

T helper 1 (TH1)-cell

The definition of a CD4+ T cell that has differentiated into a cell that produces the cytokines interferon-γ and tumour-necrosis factor.

Annexin-V

Binds to phosphatidyl serine, which is normally located on the inner leaflet of the plasma membrane, but which flips to the outer layer during apoptosis. Annexin-V staining is often used as an indicator of apoptosis.

TUNEL

An in situ method for detecting the 3′-OH ends of DNA that are exposed during the internucleosomal cleavage that occurs during apoptosis.

Small interfering RNAs

Synthetic double-stranded RNA molecules of 19–23 nucleotides, which are used to 'knock down' (silence the expression of) a specific gene. This is known as RNA interference (RNAi) and is mediated by the sequence-specific degradation of mRNA.

Myocardial depression

Patients with sepsis often have significantly decreased heart contractility that might be manifested by decreased blood pressure or shock. This decrease in heart function during sepsis is termed myocardial depression and is thought to be due, in part, to high circulating concentrations of pro-inflammatory cytokines, including tumour-necrosis factor.

AKT

(Also known as protein kinase B). A key component of the phosphatidylinositol 3-kinase signalling pathway. AKT has potent anti-apoptotic activity, and T cells that overexpress AKT are resistant to sepsis-induced apoptosis.

Cecal ligation and puncture

(CLP). CLP is a standard animal model used to induce sepsis. In the CLP model, the cecum, a large sac-like structure that is located at the junction of the small and large intestine, is occluded by suture ligation and punctured with a needle. During the subsequent time period, the animal develops intra-abdominal polymicrobial infection. The CLP model reproduces many of the signs and symptoms of sepsis that occur in patients.

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Hotchkiss, R., Nicholson, D. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 6, 813–822 (2006). https://doi.org/10.1038/nri1943

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