Sleep loss potentiates Th17‐cell pathogenicity and promotes autoimmune uveitis

Abstract

Background Sleep loss (SL) is a health issue associated with the higher risk of autoimmune and inflammatory disorders. However, the connection between SL, the immune system, and autoimmune diseases remains unknown. Methods We conducted mass cytometry, single‐cell RNA sequencing, and flow cytometry to analyze how SL influences immune system and autoimmune disease development. Peripheral blood mononuclear cells from six healthy subjects before and after SL were collected and analyzed by mass cytometry experiments and subsequent bioinformatic analysis to identify the effects of SL on human immune system. Sleep deprivation and experimental autoimmune uveitis (EAU) mice model were constructed, and scRNA‐seq data from mice cervical draining lymph nodes were generated to explore how SL influences EAU development and related autoimmune responses. Results We found compositional and functional changes in human and mouse immune cells after SL, especially in effector CD4 + T and myeloid cells. SL upregulated serum GM‐CSF levels in healthy individuals and in patients with SL‐induced recurrent uveitis. Experiments in mice undergoing SL or EAU demonstrated that SL could aggravate autoimmune disorders by inducing pathological immune cell activation, upregulating inflammatory pathways, and promoting intercellular communication. Furthermore, we found that SL promoted Th17 differentiation, pathogenicity, and myeloid cells activation through the IL‐23Th17GM‐CSF feedback mechanism, thus promoting EAU development. Lastly, an anti‐GM‐CSF treatment rescued SL‐induced EAU aggravation and pathological immune response. Conclusions SL promoted Th17 cells pathogenicity and autoimmune uveitis development, especially through the interaction between Th17 and myeloid cells involving GM‐CSF signaling, providing possible therapeutic targets for the SL‐related pathological disorders.

Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis

“…Under the stimulation of IL-23, the receptor IL-23R on the surface of CD4 + T cells transmits signals to promote Th17 cells differentiation and Th17's secretion of IL-17, GM-CSF and other pathogenic cytokines. Targeting GM-CSF inhibits Th17 cell pathogenicity and attenuates EAU severity [ 46 ]. Flow cytometry indicated that the proportion of IL-23R + and GM-CSF + Th17 cells increased by addition of IL-23, and decreased after PRG treatment (Additional file 1 : Fig.…”

Elucidating sleep disorders: a comprehensive bioinformatics analysis of functional gene sets and hub genes

“…The intimate association between sleep and the immune system suggests that SD may result in immune dysregulation ( 35 ). Murine models have shown that SD can influence the signaling of GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) by regulating Th17 and activated CD4 T cells ( 36 ), which in turn interacts with myeloid cells, exacerbating the progression of autoimmune diseases. Simple sleep deprivation in rats has been found to increase Natural Killer (NK+) and T cells (CD8+) in the spleen and decrease B cells ( 37 ).…”

GM‐CSF signalling in Th17‐cell pathogenicity: The culprit in autoimmune uveitis promoted by sleep loss

“…To this end, in the recently published article in Clinical and Translational Medicine , Liu et al 9 . simulated the condition of SL in humans and established the sleep deprivation model in mice to explore the effects of SL on immune system and EAU development.…”

“…To this end, in the recently published article in Clinical and Translational Medicine, Liu et al 9 simulated the condition of SL in humans and established the sleep deprivation model in mice to explore the effects of SL on immune system and EAU development. Based on singlecell mass cytometry by time of flight (CyTOF) and singlecell RNA sequencing (scRNA-seq), they firstly constructed an immune cell atlas of SL according to the effect of SL on healthy individuals and mice.…”