The Effect And Mechanism Of CD11c~+MHCII~+ Macrophage Liver Kinase B1 On The Development Of Chronic Pancreatitis

Objective:The etiology of chronic pancreatitis（CP）is complex and the mechanism is unclear,in which immune factors play an important role.In this study,the relationship between liver kinase B1（liver kinase B1,Lkb1）and fibrosis in paraffin tissue of CP patients was analyzed,and the CP model was established using Cd11c ^CreLkb1^f/fmice that specifically knocked out Lkb1 in CD11c⁺MHCII⁺cells to study Lkb1 To investigate the effect of Lkb1on CP fibrosis and immune cell infiltration,and to explore the effect and mechanism of Lkb1 on the occurrence and development of CP.Methods:9 cases of CP and 9 cases of normal pancreatic tissue were collected from March2018 to June 2021 in the Affiliated Hospital of Qingdao University.Expression of Lkb1,α-smooth muscle actin（α-smooth muscle actin,α-SMA）.The co-expression of CD11c,MHCII and CD68 was detected by immunofluorescence.Cd11c ^CreLkb1^f/fmice with specific knockout of Lkb1 in CD11c⁺MHCII⁺macrophages were bred,and Lkb1^f/fmice were used as controls to construct a CP model by intraperitoneal injection of cerulein.degree of transformation.Collagen fiber deposition was detected by Masson’s staining.The expressions of CD3,F4/80,α-SMA and YAP were detected by immunohistochemistry,and the infiltration of immune cells,the activation of pancreatic stellate cells and the expression of Hippo signaling pathway core protein YAP in pancreatic tissue were analyzed.The distribution of immune cells such as CD11c⁺MHCII⁺cells,macrophages,etc.in the pancreatic tissue in the experimental CP model was observed by flow cytometry.Results:By immunohistochemistry,it was found that the expression of CD11c,Lkb1 and CD68⁺macrophages were significantly increased in the pancreatic tissue of CP patients.The overlapping expressions suggest that in the pancreatitis tissue of CP patients,the cells of CD11c play an antigen-presenting role,and this part is mainly macrophages.The distribution of Lkb1 was relatively high in the fibrotic area,suggesting that Lkb1 may be involved in the process of CP fibrosis.The results of H&E staining showed that there was no significant difference in the histopathology of the pancreas between the two mice before modeling,but under the stimulation of cerulein,the CP fibrosis,pancreatic acinar atrophy and inflammatory cell infiltration in Cd11c ^CreLkb1^f/fmice were significantly aggravated.It was found accompanied by increased infiltration of F4/80⁺macrophages and CD3⁺T cells,PSC activation was significantly increased,and the expression of YAP protein in pancreatic tissue was increased.Massons staining also indicated that more collagen fibers were produced.Immunofluorescence detected the co-expression of YAP andα-SMA in the CP pancreas of Lkb1^f/fmice and Cd11c ^CreLkb1^f/fmice,and the expression of YAP was higher in the dimensional region of Cd11c ^CreLkb1^f/fmice.Flow cytometry analysis showed that the expression of CD45⁺cells in the pancreatic tissue of CP mice was significantly increased under the stimulation of cerulein,and the expression of CD11b⁺F4/80⁺macrophages was significantly increased.In addition,CD11c⁺was detected in the pancreatic tissue of the two groups of mice.MHCII⁺cells.Conclusion:1.In the pancreatitis tissue of CP patients,the expression of CD11c is increased,the expression of Lkb1 is significantly increased,and the expression of CD68⁺macrophages is significantly increased.CD11c⁺cells play an antigen-presenting role,and this part is mainly macrophages.2.Lkb1 deletion in CD11c⁺MHCII⁺macrophages aggravated pancreatic acinar cell atrophy,pancreatic interstitial fibrosis,and increased infiltration of immune cells such as macrophages in the mouse CP model,suggesting that Lkb1 may inhibit PSC activation and immune cell infiltration.The role of infiltration and CP fibrosis.3.Lkb1 deletion in CD11c⁺MHCII⁺macrophages increases the expression of YAP in the fibrotic area of pancreatic tissue in mouse CP model.Lkb1 may inhibit PSC activation through the YAP pathway of PSC and delay the progression of CP fibrosis.