p300 promotes differentiation of Th17 cells via positive regulation of the nuclear transcription factor RORγt in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) has been the major cause of acute respiratory failure in critical patients and one of the leading causes of death worldwide for several decades. Th17 cells are involved in the occurrence and progression of ARDS. Furthermore, histone acetyltransferase (HAT) p300 is a transcriptional coactivator, and its activity is closely related to cancer and inflammatory diseases. p300 and histone deacetylase 1 (HDAC1) interact with and stabilize the nuclear transcription factor retinoic acid-related orphan receptor gamma t (ROR gamma t) and participate in the regulation of ROR gamma t-mediated IL-17 transcription in T helper 17 (Th17) cell differentiation by acetylation and deacetylation. However, the effect of p300 on ROR gamma t and Th17 cells in ARDS is not well reported. Therefore, we aimed to investigate the clinical features of p300 and its effect on ROR gamma t and Th17 cells in patients with ARDS as well as in lipopolysaccharide-induced acute lung injury (ALI) mouse models. Overexpression of p300 and ROR gamma t mRNA was found in the peripheral blood mononuclear cells from patients with ARDS, especially among non-survivors, compared to that in healthy individuals (P < 0.05). Moreover, the decline of FOXP3 mRNA level correlated with survival and increased ROR gamma t mRNA levels corelated with infection (P < 0.05). Immunohistochemical analysis revealed high p300 and ROR gamma t expression in ALI mouse lung tissues. Inhibitor-mediated knockdown of p300 reduced lung tissue inflammation and lung injury score (P < 0.05). Western blotting and ELISA revealed that p300 inhibitor caused a decrease in the mRNA and protein levels of ROR gamma t as well as interleukin 17 (IL-17) production in ALI mouse lung tissues (P < 0.05). Thus, our findings suggest that p300 may play a key role in ARDS by positively regulating ROR gamma t transcription and is a potential new immunotherapy target for ARDS.