title: IRAK1-dependent signaling mediates mortality in polymicrobial sepsis.
abstract: Interleukin-1 receptor-associated kinase (IRAK1) is a key regulatory protein in TLR/IL1R-mediated cell activation during inflammatory response. Studies indicated that pending on the nature of the used inflammatory model, downregulation of IRAK1 may be beneficial or detrimental. However, the role of IRAK1 in affecting outcome in polymicrobial sepsis is unknown. We tested this question using an IRAK1-deficient mouse strain and cecal ligation and puncture (CLP) procedure, which is a clinically relevant rodent septic model. Sepsis-induced mortality was markedly lower in IRAK1-deficient mice (35 %) compared to WT (85 %). Sepsis-induced increases in blood IL-6 and IL-10 levels were blunted at 6 h post-CLP in IRAK1 deficiency compared to WT, but cytokine levels were similar at 20 h post-CLP. Sepsis-induced blood granulocytosis and depletion of splenic B cells were also blunted in IRAK1-deficient mice as compared to WT. Analysis of TLR-mediated cytokine responses by IRAK1-deficient and WT macrophages ex vivo indicated a TLR4-dependent downregulation of IL-6 and IL1β in IRAK1 deficiency, whereas TLR2-dependent responses were unaffected. TLR7/8-mediated IL-6, IL1β, and IL-10 production was also blunted in IRAK1 macrophages as compared to WT. The study shows that IRAK1 deficiency impacts multiple TLR-dependent pathways and decreases early cytokine responses following polymicrobial sepsis. The delayed inflammatory response caused by the lack of IRAK1 expression is beneficial, as it manifests a marked increased chance of survival after polymicrobial sepsis.
authors.affiliation: Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Ave., MSB G-578, Newark, NJ, 07103, USA.
authors.forename: Rachna
authors.initials: R
authors.lastname: Chandra
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federici
authors.forename: Tripti
authors.initials: T
authors.lastname: Bishwas
authors.forename: Zoltán H
authors.initials: ZH
authors.lastname: Németh
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: James A
authors.initials: JA
authors.lastname: Thomas
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Spolarics
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D060085:Coinfection / Q000276:immunology* / Q000401:mortality; D015536:Down-Regulation / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse