Sleep loss potentiates Th17‐cell pathogenicity and promotes autoimmune uveitis

Abstract

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.

Keywords

• autoimmune disease
• GM‐CSF
• mass cytometry
• myeloid cells
• single‐cell RNA sequencing
• sleep loss