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 κ-light-chain-enhancer of activated B cells (NF-κB) and
nucleotide-binding domain (
NOD)-like receptor protein 3 (NLRP3) signalling pathways leading to the upregulation and secretion of the key
cytokines interleukin (IL)-1β 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-κB
DNA-binding activity and
IL-6 secretion. Furthermore, IH significantly increased pro-IL-1β
mRNA and
protein expression and mature IL-1β 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-1β
mRNA and pro-IL-1β
protein expression. Moreover, IH-induced increase in IL-1β secretion was prevented in BMDMs isolated from NLRP3 knockout mice. Thus, targeting TLR4/NF-κB and NLRP3 signalling pathways may provide novel therapeutic options for metabolic complications in OSA.