Apoptosis and caspases regulate death and inflammation in sepsis

• Published in: Nature Reviews: Immunology 2006-11, Vol.6 (1), p.813-822
• Main Authors: Nicholson, Donald W, Hotchkiss, Richard S
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Apoptosis; Apoptosis - immunology; Autopsies; Biomedical and Life Sciences; Biomedicine; Care and treatment; Caspase Inhibitors; Caspases - metabolism; Cell Communication; Cell death; Complications and side effects; Cytokine storm; Dendritic cells; Gram-negative bacteria; Health aspects; Humans; Immune response; Immunology; Inflammation - enzymology; Inflammation - immunology; Inflammation - pathology; Inflammation - therapy; Mortality; Nosocomial infections; Protease Inhibitors - therapeutic use; Reorganization and restructuring; review-article; Sepsis; Sepsis - enzymology; Sepsis - immunology; Sepsis - pathology; Sepsis - therapy
• ISSN: 1474-1733; 1474-1741; 1365-2567
• DOI: 10.1038/nri1943

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 (T H 2) 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. An emerging concept is that sepsis is in fact due to an impaired immune response owing to excessive apoptosis of immune cells and the immunosuppressive effect that occurs as a result of the uptake of these cells. Might the use of caspase inhibitors be of therapeutic benefit in the treatment of sepsis? 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 modul