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Deletion of MyD88 markedly attenuates sepsis‐induced T and B lymphocyte apoptosis but worsens survival
Author(s) -
PeckPalmer Octavia M.,
Unsinger Jacqueline,
Chang Katherine C.,
Davis Christopher G.,
McDunn Jonathan E.,
Hotchkiss Richard S.
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0807528
Subject(s) - biology , apoptosis , sepsis , lymphocyte , immunology , cancer research , t lymphocyte , microbiology and biotechnology , immune system , genetics
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.