Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function

• Published in: Shock (Augusta, Ga.) Vol. 40; no. 2; p. 122
• Main Authors: Heffernan, Daithi S, Monaghan, Sean F, Thakkar, Rajan K, Tran, Mai L, Chung, Chun-Shiang, Gregory, Stephen H, Cioffi, William G, Ayala, Alfred
• Format: Journal Article
• Language: English
• Published: United States 01.08.2013
• Subjects: Animals; Macrophages - cytology; Macrophages - immunology; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - immunology; Mice; Mice, Inbred C57BL; Natural Killer T-Cells - cytology; Natural Killer T-Cells - immunology; Phagocytosis - physiology; Sepsis - immunology
• ISSN: 1540-0514
• DOI: 10.1097/SHK.0b013e31829ca519

Invariant natural killer T cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. Invariant natural killer T cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. Invariant natural killer T cells have been shown to modulate various mediators of the innate immune system, including macrophages. We demonstrate sepsis-inducing iNKT-cell exodus from the liver appearing in the peritoneal cavity, the source of the sepsis. This migration was affected by programmed death receptor 1. Programmed death receptor 1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT cells. Programmed death receptor 1 has been associated with markers of human critical illness. Programmed death receptor 1-deficient iNKT cells failed to demonstrate similar migration. To the extent that iNKT cells affected peritoneal macrophage function, we assessed peritoneal macrophages' ability to phagocytose bacteria. Invariant natural killer T(-/-) mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT(-/-) mice were cocultured with wild-type iNKT cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by programmed death receptor 1, and these peritoneal iNKT cells appear critical to regulation of peritoneal macrophage phagocytic function. Invariant natural killer T cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis.