Propagation of monocyte exhaustion memory and underlying mechanisms

Abstract

Monocyte exhaustion is a dysfunctional state characterized by prolonged pathogenic inflammation and immune suppression, commonly observed in chronic infections and sepsis. However, the mechanisms underlying the generation and propagation of exhausted monocytes remain poorly understood. In this study, we investigate the impacts of exhausted monocytes on neighboring naïve monocytes, endothelial cells, and T cell function. Using an in vitro co-culture system, we demonstrate that exhausted monocytes induced by prolonged LPS stimulation propagate the exhaustion phenotype to neighboring naïve monocytes. Meanwhile these exhausted monocytes can promote endothelial apoptosis, upregulate adhesion molecules ICAM-1 and VCAM-1, and enhance monocyte transmigration, contributing to endothelial dysfunction. Pharmacological inhibition of CD38, a key marker of monocyte exhaustion, significantly mitigates these effects, highlighting its critical role in monocyte-driven endothelial alterations. Furthermore, we show that exhausted monocytes suppress T cell proliferation and activation, a process reversed by CD38 inhibition. We also identify mTOR signaling as a key regulator of monocyte exhaustion and its propagation, with mTOR inhibition partially restoring monocyte functionality by downregulating exhaustion markers and STAT1/STAT3/S6K signaling. Collectively, our findings highlight the CD38-mTOR axis as a central driver of monocyte exhaustion and its pathological consequences, offering potential therapeutic targets for reversing immune dysfunction in inflammatory diseases. Graphical Abstract The inhibition of CD38 can alleviate monocyte exhaustion through suppressing the sustained mTORC1-STAT1 activation. Upon LPS stimulation, TLR4 signaling is activated through the TRAM-TRIF adaptor complex, leading to the phosphorylation of Src. This activation promotes mTORC1 signaling, characterized by the recruitment of Raptor and the activation of S6K. mTORC1 activation subsequently drives STAT1/3 signaling, which further induces CD38 expression and forms a sustained positive feedback loop. Elevated CD38 levels contribute to monocyte exhaustion by depleting NAD⁺, a key metabolic cofactor. NAD⁺ depletion negatively impacts mTORC2 signaling, leading to impaired Akt phosphorylation, resulting in diminished expression of PGC1α/β, CREB and CD86, both of which are associated with exhausted monocyte immune suppression. The CD38 inhibitor 78c disrupts this exhaustion pathway, offering a potential therapeutic strategy to mitigate monocyte dysfunction during monocyte exhaustion.