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Published online before print January 22, 2008

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(Journal of Leukocyte Biology. 2008;83:1009-1018.)
© 2008 by Society for Leukocyte Biology

Deletion of MyD88 markedly attenuates sepsis-induced T and B lymphocyte apoptosis but worsens survival

Octavia M. Peck-Palmer^*,, Jacqueline Unsinger^*, Katherine C. Chang^*, Christopher G. Davis^*, Jonathan E. McDunn^* and Richard S. Hotchkiss^*,,,1

^* Departments of Anesthesiology,
Surgery,
Medicine, and
Pathology/Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA

¹ Correspondence: Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8054, St. Louis, MO 63110, USA. E-mail: hotch{at}wustl.edu

Sepsis induces widespread lymphocyte apoptosis, resulting in impaired immune defenses and increased morbidity and mortality. There are multiple potential triggers or signaling molecules involved in mediating death signals. Elucidating the specific signaling pathways that are involved in mediating lymphocyte apoptosis may lead to improved therapies of this lethal disorder. We investigated a number of key cellular receptors and intracellular signaling pathways that may be responsible for apoptotic cell death. Specifically, we investigated the role of pathogen-associated molecular patterns (TLR2, TLR4, and IL-1R), intracellular signaling proteins (MyD88 and TRIF), cytoplasmic transcription factors (STAT1 and STAT4), and the MAPK pathway (JNK1) in sepsis-induced lymphocyte apoptosis. Studies were performed in the cecal ligation and puncture (CLP) model of sepsis using specific gene-targeted deletions. CLP-induced lymphocyte apoptosis was evaluated 20 h post-operation by active caspase-3 and TUNEL staining. Surprisingly, the only genetic construct that ameliorated T and B lymphocyte sepsis-induced apoptosis (80% and 85%, respectively) occurred in MyD88^–/– mice. Despite the marked decrease in sepsis-induced apoptosis, MyD88^–/– mice had a worsened survival. In conclusion, lymphocyte death in sepsis likely involves multiple pathogen-sensing receptors and redundant signaling pathways. MyD88 was effective in blocking apoptosis, as it is essential in mediating most pathogen recognition pathways; however, MyD88 is also critical for host survival in a model of severe peritonitis.

Key Words: cell death • cytokines • cell signaling • endotoxin