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Complete dependence on IRAK4 kinase activity in TLR2, but not TLR4, signaling pathways underlies decreased cytokine production and increased susceptibility to Streptococcus pneumoniae infection in IRAK4 kinase-inactive mice.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2013 Jan 01; Vol. 190 (1), pp. 307-16. Date of Electronic Publication: 2012 Dec 03. - Publication Year :
- 2013
-
Abstract
- IRAK4 is critical for MyD88-dependent TLR signaling, and patients with Irak4 mutations are extremely susceptible to recurrent bacterial infections. In these studies, mice homozygous for a mutant IRAK4 that lacks kinase activity (IRAK4(KDKI)) were used to address the role of IRAK4 in response to TLR agonists or bacterial infection. IRAK4(KDKI) macrophages exhibited diminished responsiveness to the TLR4 agonist LPS and little to no response to the TLR2 agonist Pam3Cys compared with wild-type macrophages as measured by cytokine mRNA, cytokine protein expression, and MAPK activation. Importantly, we identified two kinases downstream of the MAPKs, MNK1 and MSK1, whose phosphorylation is deficient in IRAK4(KDKI) macrophages stimulated through either TLR2 or TLR4, suggesting that IRAK4 contributes to TLR signaling beyond the initial phosphorylation of MAPKs. Additionally, IRAK4(KDKI) macrophages produced minimal cytokine mRNA expression in response to the Gram-positive bacteria Streptococcus pneumoniae and Staphylococcus aureus compared with WT cells, and IRAK4(KDKI) mice exhibited increased susceptibility and decreased cytokine production in vivo upon S. pneumoniae infection. Treatment of infected mice with a complex of polyinosinic-polycytidylic acid with poly-L-lysine and carboxymethyl cellulose (Hiltonol), a potent TLR3 agonist, significantly improved survival of both WT and IRAK4(KDKI) mice, thereby providing a potential treatment strategy in both normal and immunocompromised patients.
- Subjects :
- Animals
Cells, Cultured
Cytokines genetics
Down-Regulation immunology
Genetic Predisposition to Disease
Humans
Interleukin-1 Receptor-Associated Kinases deficiency
Interleukin-1 Receptor-Associated Kinases genetics
Macrophages, Peritoneal enzymology
Macrophages, Peritoneal immunology
Macrophages, Peritoneal pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Pneumococcal Infections enzymology
Pneumococcal Infections genetics
Signal Transduction genetics
Cytokines antagonists & inhibitors
Cytokines biosynthesis
Interleukin-1 Receptor-Associated Kinases metabolism
Pneumococcal Infections immunology
Signal Transduction immunology
Toll-Like Receptor 2 physiology
Toll-Like Receptor 4 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 190
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 23209321
- Full Text :
- https://doi.org/10.4049/jimmunol.1201644