IRAK4 activity controls immune responses to intracellular bacteria Listeria monocytogenes and Mycobacterium smegmatis

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Goutham Pattabiraman¹  Michael Murphy¹  Federica Agliano¹  Keaton Karlinsey¹  Andrei E. Medvedev¹ 

[1] Department of Immunology, University of Connecticut Health Center, Farmington

关键词: inflammation;    innate immunity;    infection;    TLR;    macrophage;   

DOI  :  10.1002/JLB.2A1117-449R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

IL-1 receptor-associated kinase (IRAK) 4 is a central enzyme of the TLR pathways. This study tested the hypothesis that IRAK4 kinase activity is prerequisite for regulating innate immunity during infections with intracellular bacteria. To this end, we analyzed responses of macrophages obtained from mice expressing wild-type (WT) IRAK4 or its kinase-inactive K213M mutant (IRAK4KI) upon infection with intracellular bacteria Listeria monocytogenes or Mycobacterium smegmatis. In contrast to robust induction of cytokines by macrophages expressing kinase-sufficient IRAK4, IRAK4KI macrophages expressed decreased TNF-?, IL-6, IL-1?, and C-C motif chemokine ligand 5 upon infection with L. monocytogenes or M. smegmatis. Bacterial infection of IRAK4KI macrophages led to attenuated activation of IRAK1, MAPKs and NF-?B, impaired induction of inducible NO synthase mRNA and secretion of NO, but resulted in elevated microbial burdens. Compared with WT animals, systemic infection of IRAK4KI mice with M. smegmatis or L. monocytogenes resulted in decreased levels of serum IL-6 and CXCL-1 but increased bacterial burdens in the spleen and liver. Thus, a loss of IRAK4 kinase activity underlies deficient cytokine and microbicidal responses during infection with intracellular bacteria L. monocytogenes or M. smegmatis via impaired activation of IRAK1, MAPKs, and NF-?B but increases bacterial burdens, correlating with decreased induction of NO.

【 授权许可】

CC BY