Role Of Cecum In TNF-?-induced Systemic Inflammation

The multifunction cytokine TNF-a plays an important role in the immune inflammatory response,it can induce programmed cell necrosis and accelerate the body's inflammatory response.When the inflammatory response became excessive and out of control,it leads to systemic inflammatory response syndrome(SIRS),which is a dangerous disease in clinical,especially in ICU.RIP3 and MLKL play important roles in TNF-a-induced necrosis and deletion of RIP3 or MLKL can inhibit TNF-a-induced cell necrosis in vitro or in vivo.After TNF-a injection,a large number of Rip3 and Mlk1-dependent programmed necrosis(collectively referred as necroptosis)occurs in the cecum epithelial cells in mice,and the cecum damage lesions reduced in Rip3 or Mlkl knockout mice.To investigate whether the caecum necroptosis determines the pathological effect of TNF-a in mice,we performed cecum resection surgery in mice.After a month's recovery,we injected the surgery group and sham group with TNF-a,and found that the absence of cecum significantly inhibited TNF-a induced mice death.These results confirm that cecum necroptosis play an important role in TNF-? induced systemic inflammatory responses in mice.Although a small number of bacteria can be detected in the blood after TNF-a injection,the invasion bacteria number in blood has no significant difference between the cecum resection group and the sham group.So,the bacterial invasion is not the cause of subsequent systemic inflammatory reactions.When analyzing the pathology character changes of major organs after TNF-? injection,severe kidney and heart damage are observed in shame groups,and both kidney and heart damage in the cecum-removed mice are significantly improved.Heart and kidney play important role in circulation system and body homeostasis.Therefore,we speculate that RIP3 and MLKL-dependent necroptosis induced by TNF-a contributes to the damage of heart and kidney,finally cause the death of mice.We also established an acute appendicitis model in mice,and a large number of phosphorylated Rip3 positive epithelial cells are observed in this acute appendicitis model.However,the absence of Rip3 did not affect the progression of acute appendicitis pathology in mice.Although the detailed role of Rip3-dependent necroptosis in the pathogenesis of acute appendicitis remains to be explored,the study of necroptosis in cecum epithelial cells will provide new ideas for the treatment of systemic inflammatory reactions in clinical practice.