Liver failure, including acute, chronic, and acute-on-chronic liver failure, is a rare but dramatic clinical syndrome characterized by massive hepatocyte death and overactivation of hepatic inflammation[1]. Acute-on-chronic liver failure (ACLF), characterized by an acute deterioration of liver function in patients with pre-existing chronic liver disease, usually results in hepatocellular dysfunction and carries a high mortality rate[2]. Apart from liver transplantation, few effective therapies are available, and ACLF continues to be a huge therapeutic challenge[3]. The precise molecular mechanisms for the pathogenesis of ACLF have not been clarified, exploring ACLF-associated molecules may enable the development of strategies to improve the prognosis for patients with ACLF.
Hepatic stellate cells (HSCs) are resident mesenchymal cells that have features of fibroblasts and pericytes, and account for 15% of total resident cells in normal human liver[4]. HSCs are key nonparenchymal components in the sinusoid with multiple functions[5]. Some recent studies have revealed that activated HSCs may release inflammatory cytokines like interleukin (IL)-1β and IL-18, and HSCs inflammation has been shown participated in the pathogenesis of several liver diseases: HSCs of murine or human origin produce inflammatory cytokines promoting hepatocellular carcinoma and immune-mediated hepatitis[6], our previous study has shown that HSCs inflammation participates in disease pathogenesis of ALF[7].
Autophagy is a conserved process by which cytoplasmic components, including damaged proteins and organelles, are degraded by lysosomes[8]. Autophagy and inflammation are highly intertwined cellular process. Autophagy suppresses proinflammatory process and inflammasome activity[9]. Decreased autophagy was found leading to elevated hepatic inflammation promoting the progression of alcoholic liver disease[10], and LPS & D-GalN induced liver injury in mice[11]. Inflammatory cytokines also function to reciprocally control autophagy[9]. However, the mechanisms by which inflammatory signals specifically relieve the negative suppression by autophagy on HSCs inflammation during ACLF remains unknown.
Mitogen-activated protein kinase (MAPK), including p38, ERK and c-JNK are members of a ubiquitous protein serine/threonine kinase family responsible for signal transduction in eukaryotic organisms[12]. MAPK activation is implicated in the production of many inflammatory mediators[13]. Mammalian genomes encode four distinct p38 MAPK isoforms, including α, β, γ and δ. MAPK p38α and β are commonly activated by stressful or pro-inflammatory stimuli[14]. Most studies of p38 MAPK have focused on its functions in inflammatory cells during the pathogenesis of inflammation dependent diseases, including rheumatoid arthritis, Crohn’s disease, psoriasis and asthma[15, 16].
In the present study, we show that p38 MAPK plays an essential role in relieving autophagic control in response to inflammatory signal. We found elevated expression of p38 MAPK in liver tissues from patients with ACLF. Stimulation of LPS inhibits autophagy via p38 MAPK, this inhibition is necessary for LPS-induced inflammasome activation in LX2 cells. We show that p38 MAPK directly interacts with Atg13, phosphorylates Atg13 and reduces Atg13-ULK1 interaction.