PMID- 29515583
OWN - NLM
STAT- MEDLINE
DCOM- 20190321
LR  - 20221009
IS  - 1664-3224 (Print)
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 9
DP  - 2018
TI  - K63-Linked Polyubiquitination on TRAF6 Regulates LPS-Mediated MAPK Activation, 
      Cytokine Production, and Bacterial Clearance in Toll-Like Receptor 7/8 Primed 
      Murine Macrophages.
PG  - 279
LID - 10.3389/fimmu.2018.00279 [doi]
LID - 279
AB  - Post viral infection bacterial pneumonia is a major cause of morbidity and 
      mortality associated with both seasonal and pandemic influenza virus illness. 
      Despite much efforts put into the discovery of mechanisms of post viral-bacterial 
      infections and their complications in recent years, the molecular mechanisms 
      underlying the increased susceptibility to bacterial infection remain poorly 
      understood. In this study, we focused on the pathways regulating immune responses 
      in murine macrophages and modeled post viral-bacterial infections through 
      pretreatment of bone marrow-derived macrophages (BMDMs) with a toll-like receptor 
      (TLR) 7/8 ligand (R848) and subsequent challenge with TLR2/4 agonists to mimic 
      bacterial infection. We found R848-primed BMDMs upon subsequent exposure to 
      TLR2/4 ligands respond with enhanced inflammatory cytokine production, especially 
      IL-6 and TNF-alpha. The enhanced cytokine production in R848-primed BMDMs in response 
      to TLR2/4 was due to increased TGF-beta-activated kinase (TAK) 1 phosphorylation 
      with subsequent activation of ERK and p38 MAPKs. Furthermore, we identified that 
      R848 priming leads to increased K63-linked polyubiquitination on TRAF6. 
      K63-linked polyubiquitination on TRAF6 is a signal leading to enhanced activation 
      of downstream pathways including TAK1. Importantly, R848-primed BMDMs infected 
      with live bacteria exhibited decreased bacterial clearance. Small-molecule 
      enhancer of rapamycin 3, an ubiquitin ligase inhibitor reversed the K63-linked 
      polyubiquitination on TRAF6 in R848-primed BMDMs and subsequently decreased TAK1 
      and MAPK phosphorylation, and cytokine production as well as reversed the 
      decreased bacterial clearance capacity of BMDMs. Our study may provide a novel 
      molecular target to alleviate post viral-bacterial infections.
FAU - Talreja, Jaya
AU  - Talreja J
AD  - Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep 
      Medicine, Wayne State University School of Medicine, Detroit Medical Center, 
      Detroit, MI, United States.
FAU - Samavati, Lobelia
AU  - Samavati L
AD  - Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep 
      Medicine, Wayne State University School of Medicine, Detroit Medical Center, 
      Detroit, MI, United States.
AD  - Center for Molecular Medicine and Genetics, Wayne State University School of 
      Medicine, Detroit, MI, United States.
LA  - eng
GR  - R01 HL113508/HL/NHLBI NIH HHS/United States
GR  - R01 HL150474/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180221
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (TLR8 protein, mouse)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 0 (Tlr7 protein, mouse)
RN  - 0 (Toll-Like Receptor 7)
RN  - 0 (Toll-Like Receptor 8)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - Cytokines/*biosynthesis
MH  - Extracellular Signal-Regulated MAP Kinases/*immunology
MH  - Lipopolysaccharides/immunology
MH  - Macrophages/*immunology
MH  - Membrane Glycoproteins/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Pneumonia, Bacterial/*immunology
MH  - TNF Receptor-Associated Factor 6/immunology/*metabolism
MH  - Toll-Like Receptor 7/immunology
MH  - Toll-Like Receptor 8/immunology
MH  - Ubiquitination
MH  - Virus Diseases/complications/immunology
PMC - PMC5826352
OTO - NOTNLM
OT  - bone marrow-derived macrophages
OT  - post viral-bacterial infection
OT  - priming
OT  - toll-like receptor 2
OT  - toll-like receptor 4
OT  - toll-like receptor 7/8
OT  - ubiquitination
EDAT- 2018/03/09 06:00
MHDA- 2018/03/09 06:01
PMCR- 2018/01/01
CRDT- 2018/03/09 06:00
PHST- 2017/09/18 00:00 [received]
PHST- 2018/01/31 00:00 [accepted]
PHST- 2018/03/09 06:00 [entrez]
PHST- 2018/03/09 06:00 [pubmed]
PHST- 2018/03/09 06:01 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2018.00279 [doi]
PST - epublish
SO  - Front Immunol. 2018 Feb 21;9:279. doi: 10.3389/fimmu.2018.00279. eCollection 
      2018.