PMID- 32996666
OWN - NLM
STAT- MEDLINE
DCOM- 20210713
LR  - 20210713
IS  - 1365-2869 (Electronic)
IS  - 0962-1105 (Linking)
VI  - 30
IP  - 3
DP  - 2021 Jun
TI  - Mechanisms of intermittent hypoxia-mediated macrophage activation - potential 
      therapeutic targets for obstructive sleep apnoea.
PG  - e13202
LID - 10.1111/jsr.13202 [doi]
AB  - Intermittent hypoxia (IH) plays a key role in the pathogenesis of insulin 
      resistance (IR) in obstructive sleep apnoea (OSA). IH induces a pro-inflammatory 
      phenotype of the adipose tissue with M1 macrophage polarisation, subsequently 
      impeding adipocyte insulin signalling, and these changes are in striking 
      similarity to those seen in obesity. However, the detailed molecular mechanisms 
      of IH-induced macrophage polarisation are unknown and identification of same 
      should lead to the identification of novel therapeutic targets. In the present 
      study, we tested the hypothesis that IH acts through similar mechanisms as 
      obesity, activating Toll-like-receptor (TLR)4/nuclear factor 
      kappa-light-chain-enhancer of activated B cells (NF-kappaB) and nucleotide-binding domain 
      (NOD)-like receptor protein 3 (NLRP3) signalling pathways leading to the 
      upregulation and secretion of the key cytokines interleukin (IL)-1beta and IL-6. 
      Bone-marrow derived macrophages (BMDMs) from lean and obese C57BL/6 male mice 
      were exposed to a state-of-the-art in vitro model of IH. Independent of obesity, 
      IH led to a pro-inflammatory M1 phenotype characterised by increased inducible 
      nitric oxide synthase and IL-6 mRNA expression, robust increase in NF-kappaB 
      DNA-binding activity and IL-6 secretion. Furthermore, IH significantly increased 
      pro-IL-1beta mRNA and protein expression and mature IL-1beta secretion compared to 
      control treatment. Providing mechanistic insight, pre-treatment with the TLR4 
      specific inhibitor, TAK-242, prevented IH-induced M1 polarisation and 
      upregulation of IL-1beta mRNA and pro-IL-1beta protein expression. Moreover, IH-induced 
      increase in IL-1beta secretion was prevented in BMDMs isolated from NLRP3 knockout 
      mice. Thus, targeting TLR4/NF-kappaB and NLRP3 signalling pathways may provide novel 
      therapeutic options for metabolic complications in OSA.
CI  - (c) 2020 European Sleep Research Society.
FAU - Fitzpatrick, Susan F
AU  - Fitzpatrick SF
AD  - School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland.
FAU - King, Ailbhe D
AU  - King AD
AD  - School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland.
FAU - O'Donnell, Cliona
AU  - O'Donnell C
AD  - Pulmonary and Sleep Disorders Unit, St Vincent's University Hospital, Dublin, 
      Ireland.
FAU - Roche, Helen M
AU  - Roche HM
AD  - Nutrigenomics Research Group, School of Public Health, Physiotherapy and Sports 
      Science, UCD Institute of Food and Health, Diabetes Complications Research 
      Centre, University College Dublin, Dublin, Ireland.
AD  - Institute for Global Food Security, Queen's University Belfast, Belfast, UK.
FAU - Ryan, Silke
AU  - Ryan S
AUID- ORCID: 0000-0003-0963-255X
AD  - School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland.
AD  - Pulmonary and Sleep Disorders Unit, St Vincent's University Hospital, Dublin, 
      Ireland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200930
PL  - England
TA  - J Sleep Res
JT  - Journal of sleep research
JID - 9214441
SB  - IM
MH  - Animals
MH  - Macrophage Activation/*physiology
MH  - Male
MH  - Mice
MH  - Sleep Apnea, Obstructive/*therapy
OTO - NOTNLM
OT  - IL-1beta
OT  - NLRP3 inflammasome
OT  - Toll-like-receptor 4
OT  - intermittent hypoxia
OT  - macrophages
OT  - obstructive sleep apnoea
EDAT- 2020/10/01 06:00
MHDA- 2021/07/14 06:00
CRDT- 2020/09/30 08:45
PHST- 2020/08/31 00:00 [revised]
PHST- 2020/07/17 00:00 [received]
PHST- 2020/09/06 00:00 [accepted]
PHST- 2020/10/01 06:00 [pubmed]
PHST- 2021/07/14 06:00 [medline]
PHST- 2020/09/30 08:45 [entrez]
AID - 10.1111/jsr.13202 [doi]
PST - ppublish
SO  - J Sleep Res. 2021 Jun;30(3):e13202. doi: 10.1111/jsr.13202. Epub 2020 Sep 30.