CD11cCD69trained 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-αmice were exposed to OVA. CD11cCD69APCs induced by OVA were re-stimulated by lipopolysaccharide to investigate trained immunity. The effect of histone acetylation in CD11cCD69trained APCs were determined in vivo and in vitro. Epigenetic inhibitors, TNF-αmice, and adoptive transfer were used to explore the development and function of these cells in mice. RESULTS: OVA induced CD11cCD69trained APCs, which showed stronger responses and lipid metabolic reprogramming characterized by increased acetylcarnitine, a source of acetyl, compared with CD11cCD69APCs in mice. CD11cCD69trained APCs showed the histone acetylation marker H3K27ac. H3K27ac was enriched at the CD69 gene in CD11cCD69trained APCs, which supported CD69 expression. Histone acetyltransferase inhibitor inhibited development of CD11cCD69trained APCs. Functionally, CD11cCD69trained APCs promoted Th2-type response. Adoptively transferred CD11cCD69trained APCs, but not CD11cCD69APCs, 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-αmice 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 CD11cCD69trained APCs in asthma, and demonstrated that histone acetylation supported CD11cCD69trained APCs to mediate asthma. The result may provide a potential target for the treatment of asthma.