Systemic depletion of CD11b+ cells improves metabolic function in murine model of sleep apnea induced by intermittent hypoxia.

Intermittent hypoxia (IH), a hallmark feature of obstructive sleep apnea (OSA), is associated with a range of physiological alterations that contribute to metabolic dysfunction and insulin resistance. IH induces adipose tissue inflammation and macrophages may play a key role in such homeostatic derangements. To examine the role of monocytes/macrophages in OSA, CD11b-diphtheria toxin receptor (DTR) transgenic mice were treated with diphtheria toxin to selectively eliminate these cells and assess changes in the metabolic function of IH-exposed mice. Transgenic homozygous male and female DTR mice were exposed to IH or room air (RA) for 6 weeks, during which insulin sensitivity and other metabolic measures were assessed. Immunofluorescence analysis was performed for CD11b+ expression in metabolic tissues such as the liver and visceral white adipose tissue (vWAT). Gene expression patterns associated with senescence-associated secretory phenotypes (SASPs) as well as adipokines and cytokines were evaluated. Depletion of CD11b+ cells in mice exposed to IH resulted in significant improvements in metabolic function and insulin sensitivity. Macrophage infiltration, assessed by F4/80 or CD11b immunostaining, was significantly reduced following CD11b ablation in IH-exposed mice compared with controls in both males and females. Moreover, CD11b+ cell ablation led to a marked decrease in SASPs markers (p16 and Il-16) at both transcriptional and protein levels in vWAT and the liver. Thus, depletion of CD11b+ cells in mice exposed to IH can significantly modulate the inflammatory response in multiple metabolic organs, including visceral adipose tissues, and markedly mitigate metabolic dysfunction. Targeted interventions aimed at some of the functional roles played by activated CD11b+ cells or SASPs within metabolic organs may improve metabolic regulation in people with OSA. Statement of Significance Obstructive sleep apnea (OSA) is strongly associated with insulin resistance and metabolic dysfunction, yet the cellular drivers of these complications are not well defined. This study identifies CD11b+ monocytes and macrophages as central mediators of the inflammatory and metabolic disturbances caused by intermittent hypoxia (IH), a defining feature of OSA. Using a transgenic mouse model that enables selective depletion of CD11b+ cells, we show that removal of this immune population markedly improves insulin sensitivity and reduces markers of inflammation and senescence in tissues such as the liver and visceral white adipose tissue. These findings identify CD11b+ myeloid cells as key contributors to IH-induced metabolic dysfunction and highlight both these cells and their downstream inflammatory pathways as promising therapeutic targets. Targeting this immune axis may offer a new strategy to improve metabolic health in people with OSA.