IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling.
Lujing ShaoXi XiongYucai ZhangHuijie MiaoYuqian RenXiaomeng TangJia SongChunxia WangPublished in: Cell death & disease (2020)
Uncontrollable inflammatory response acts as a driver of sepsis-associated liver injury (SALI). IL-22 plays an important role in regulating inflammatory responses, but its role in SALI remains unknown. The aim of the study was to assess the association of serum IL-22 with SALI in pediatric patients and to enclose the underlying mechanisms of IL-22 involved in lipopolysaccharide (LPS) - induced acute liver injury (ALI) in mice. Serum IL-22 levels in patients with SALI were significantly lower than in septic patients without liver injury, and the area under receiver operating characteristic (ROC) curve of IL-22 for discriminating SALI was 0.765 (95% CI: 0.593-0.937). Pre-administration of recombinant murine IL-22 alleviated LPS-induced ALI in mice, and serum IL-6 levels and the mRNA levels of TNF-α, IL-1β, and IL-6 in livers were decreased in response to IL-22 pre-treatment in mice. More importantly, IL-22 pre-treatment activated hepatic autophagy mediated by activating transcription factor 4 (ATF4)-autophagy-related gene 7 (ATG7) signaling in vivo and in vitro in response to LPS administration. Moreover, knockdown of ATF4 in mice aggravated LPS-induced ALI, which was associated with suppressed ATG7-related autophagy. In addition, the protective effects of IL-22 on LPS-induced ALI was partially blocked by ATF4 knockdown, which was associated with lower expression of LC3II/I in the livers of ATF4 knockdown (HT or Atf4+/-) mice compared with wild-type mice (WT or Atf4+/+) mice. In conclusion, low serum IL-22 level is associated with SALI occurrence, and IL-22 pre-administration activates autophagy in hepatocytes and protects mice against LPS-induced ALI partially related to ATF4-ATG7 signaling pathway.
Keyphrases
- lps induced
- inflammatory response
- liver injury
- drug induced
- transcription factor
- endoplasmic reticulum stress
- signaling pathway
- wild type
- high fat diet induced
- cell death
- lipopolysaccharide induced
- oxidative stress
- rheumatoid arthritis
- acute kidney injury
- intensive care unit
- poor prognosis
- type diabetes
- gene expression
- end stage renal disease
- immune response
- induced apoptosis
- chronic kidney disease
- skeletal muscle
- hepatitis b virus
- long non coding rna
- simultaneous determination
- binding protein
- mechanical ventilation
- extracorporeal membrane oxygenation
- patient reported outcomes