Identifying LKB1 And LRRK2 As Important Players In Inflammatory Diseases

Liver kinase B1?LKB1?,also named as Serine/Theronine kinase 11?STK11?,is widely known as a tumor suppressor.Truncating germline mutations of LKB1 lead to about 66-94%cases of Peutz-Jeghers syndrome?PJS?.PJS is an autosomal dominant genetic disease which is also named as hereditary intestinal polyposis syndrome.Patients of PJS are marked by cutaneous pigmentation of mucusmembrane as well as development of benign hamartomatous polyps in the gastrointestinal tract.Another key feature of PJS is greatly increased risk of developing malignant tumors of multiple tissues,especially in the gastrointestinal tract.Even though,inflammation has been implicated in the pathogenesis of polyposis in PJS,how LKB1 affect inflammatory response remain largely unknown.Using intestinal-epithelial cell specific LKB1 knockout mice(Villin^cre/+LKB1^fl/fl,shorts as LKB1^?IEC),we found that specific deletion of LKB1 in the intestinal epithelium results in aberrant intestinal epithelium in which the number of goblet cell is greatly increased.But the aberrant intestinal epithelium doesn't lead to spontaneous intestinal inflammation nor tumor development.However,specific deletion of LKB1 in the intestinal epithelium renders mice more susceptible to DSS induced acute colitis as well as AOM+DSS induced colitis-associated colon cancer.What's more,epithelium LKB1 deficiency promotes colitis doesn't dependent on the classic LKB1-AMPK-mTORC1 signaling pathway.Further research revealed that specific deletion of LKB1 in the intestinal epithelial cells impairs IL-18 and IL-18-target antimicrobial peptide production by intestinal epithelial cells on na?ve condition,which also leads to dysbiosis in the LKB1^?IEC mice.Pyrosequencing of 16S rRNA on the fecal samples revealed a dramatic decrease in Bacteroides,Fimicutes and Lactobacillus while an outgrowth of Proteobacteria,Actinobactreria and Prevotella in the LKB1-deficient mice.Exacerbated colitis severity of gut epithelial-specific LKB1-deficient mice is transmissible to co-housed wild-type control mice.Also,fecal microbiota transplantation experiment demonstrated that wild type mice received feces from LKB1-deficient mice exhibited much severer colitis compared to the wild type mice received feces from the control mice in response to DSS induced acute colitis.Means gut microbiota from LKB1-deficient mice is colitogenic.Taken together,our research revealed a novel mechanism by which LKB1 expression in intestinal epithelial cells influence the composition of resident bacterial community to suppress the susceptibility to colitis and colitis-associated tumorigenesis.Leucine-rich repeat kinase 2?LRRK2?mutations are the most prevalent genetic cause of Parkinson's disease?PD?.Emerging data suggest critical roles of LRRK2 in immunity though the exact mechanisms remain largely unknown.IL-1?has been associated with PD.Inflammasomes mediate activation of caspases which promote secretion of proinflammatory cytokines IL-1?and IL-18,and pyroptosis.Here we examined LRRK2 in inflammasome activation.LRRK2 deficiency dramatically alleviated NLRC4 inflammasome activation in bone marrow derived macrophages?BMDMs?upon S.typhimurium infection.Furthermore,we demonstrated that LRRK2-deficient mice were more susceptible to S.typhimurium infection with less IL-1?production in serum and peritoneal fluid comparing to that of wild-type controls.Taken together,our results suggest an important role of LRRK2 in inflammasomes activation,implicating a mechanism in PD pathogenesis.