ATF3 deficiency promotes alveolar macrophage pyroptosis in sepsis-induced acute lung injury

Acute lung injury (ALI) ranks among the leading reasons for death in septic patients. As an essential transcription factor associated with stress, activating transcription factor 3 (ATF3) participates in a variety of pathophysiological processes, including immunology and inflammation. However, the specific mechanism of ATF3 in pyroptosis of sepsis-induced ALI remains elusive.

A mouse model of ALI was established by administering lipopolysaccharide (LPS) in vivo and LPS combined with adenosine triphosphate (ATP) in vitro to compare differences in ATF3 expression level. The role of ATF3 in pyroptosis was then assessed by knocking down ATF3 using small interfering RNA. The levels of interleukin-6 (IL-6), tumor necrosis factor-α, IL-1β, and IL-18 in mouse serum and cell culture supernatants were measured using enzyme-linked immunosorbent assay. Moreover, immunohistochemistry, immunofluorescence, Western blotting, co-immunoprecipitation, and quantitative reverse transcription polymerase chain reaction were employed for examining pyroptosis and pyroptotic pathways.

Both in vitro and in vivo ALI models were successfully established. LPS could activate the pyroptotic signaling pathway, and the expression level of ATF3 peaked 6 h after LPS and ATP stimulation in vitro. ATF3 could interact with NLRP3 and potentially influence the assembly of the inflammasome. This mechanism could involve the inhibition of the classical pyroptotic pathway, including Caspase-1 and Gasdermin D transcription and cleavage, as well as the inhibition of the non-classical pyroptotic pathway, including transcription and cleavage of Caspase-11.

The results indicated that inhibition of ATF3 could exacerbate sepsis-induced ALI by regulating pyroptotic pathways. The potential of targeting ATF3 as a future treatment strategy for ALI is noteworthy.