CD11c+CD69+ trained APCs in lungs mediate allergic asthma through increased H3K27ac

Abstract

Objective: Investigating the impact and mechanism of trained antigen-presenting cells (APCs) in asthma in ovalbumin (OVA)-sensitized mouse model and discovering targets for treating asthma.

Methods: BALB/c and C57BL/6 J wild-type mice and TNF-α^-/- mice were exposed to OVA. CD11c⁺CD69⁺ APCs induced by OVA were re-stimulated by lipopolysaccharide to investigate trained immunity. The effect of histone acetylation in CD11c⁺CD69⁺ trained APCs were determined in vivo and in vitro. Epigenetic inhibitors, TNF-α^-/- mice, and adoptive transfer were used to explore the development and function of these cells in mice.

Results: OVA induced CD11c⁺CD69⁺ trained APCs, which showed stronger responses and lipid metabolic reprogramming characterized by increased acetylcarnitine, a source of acetyl, compared with CD11c⁺CD69^- APCs in mice. CD11c⁺CD69⁺ trained APCs showed the histone acetylation marker H3K27ac^high. H3K27ac was enriched at the CD69 gene in CD11c⁺CD69⁺ trained APCs, which supported CD69 expression. Histone acetyltransferase inhibitor inhibited development of CD11c⁺CD69⁺ trained APCs. Functionally, CD11c⁺CD69⁺ trained APCs promoted Th2-type response. Adoptively transferred CD11c⁺CD69⁺ trained APCs, but not CD11c⁺CD69^- APCs, induced asthma. Inhibition of histone acetyltransferase prevented asthma. Further, TNF-α expression increased in asthmatic mice or patients. H3K27ac maintained TNF-α production in the trained APCs. TNF-α^-/- mice showed attenuated asthma, whereas adoptive transfer of the trained APCs restored asthma, suggesting a key role of TNF-α for the function of the trained APCs.

Conclusion: We discovered a crucial role of CD11c⁺CD69⁺ trained APCs in asthma, and demonstrated that histone acetylation supported CD11c⁺CD69⁺ trained APCs to mediate asthma. The result may provide a potential target for the treatment of asthma.

Keywords: Allergic asthma; H3K27ac; Metabolic reprogramming; TNF-α; Trained APCs.