| The survival of human is threatened by infectious diseases caused by pathogens.Innate immunity is treated as the first line of defense against pathogenic microorganisms,which recognizes and eliminates pathogens.Autophagy,a catabolic process mediated by lysosomes,plays a significant role in innate immunity by effectively degrading intracellular pathogens,including the bacterium S.Typhimurium.In daily life,oral iron supplementation can effectively alleviate iron deficiency.However,excessive intake of iron may lead to infectious diseases.Excessive iron alters the species and quantities of microorganisms in the intestine of the host,in which a lot of pathogenic microorganisms proliferate and increase the possibility of diarrhea.Nevertheless,the effect of excessive iron supplementation on host immune defense is not fully understood.In order to prevent the pathogen from invading,the host adopts the defensive way called as nutritional immunity,which binds and detains iron with the high affinity proteins to restrict the pathogens using the metal as nutrition source.Ferritin is mainly responsible for the storage of iron ions in host cells.However,it is poorly understood whether Ferritin in intestinal epithelial cells is involved in host resistance against pathogens.In this study,utilizing C.elegans and Caco-2 epithelial cell lines as models,we explored the nutritional immune defense mechanism initiated by the host infected with S.Typhimurium under iron overload conditions.Our results indicated that S.Typhimurium infection promoted autophagy,which mediated the resistance to S.Typhimurium in C.elegans.When autophagy was activated,FTN in intestinal epithelial cells of C.elegans did not participate in the resistance to S.Typhimurium.However,iron supplementation inhibited autophagy induced by S.Typhimurium,increased susceptibility to S.Typhimurium and promoted mortality of C.elegans.When iron was overloaded,the level of FTN protein was up-regulated by the suppression of autophagy.By binding and storing iron ions,FTN protein in intestinal epithelial cells of C.elegans restricted the utilization of iron sources by S.Typhimurium.When iron was overloaded,FTN mediated nutritional immunityagainst S.Typhimurium in C.elegans.In addition,our results showed that ERK was involved in the activation of autophagy and innate immune responses to S.Typhimurium,and negatively regulated FTN protein levels.Iron inhibited autophagy by suppressing the ERK pathway in C.elegans exposure to S.Typhimurium.The nutritional immune signaling pathway mediated by FTN in C.elegans was conserved in mammals.Our data from human intestinal Caco-2 cells showed that autophagy was required for resistance against S.Typhimurium in Caco-2 cells.Meanwhile,ERK mediated the activation of autophagy in cells after S.Typhimurium infection.Autophagy suppressed the level of Ferritin protein in Caco-2 cells.However,iron overload suppressed autophagy in Caco-2 cells induced by S.Typhimurium.A number of S.Typhimurium was accumulated in Caco-2 cells,which enhanced susceptibility to S.Typhimurium and mortality rate of Caco-2 cells.The level of Ferritin in Caco-2 cells was up-regulated by the inhibition of autophagy.Ferritin mediated the resistance to S.Typhimurium by chelating iron in Caco-2 cells.In conclusion,the host sets up different “barriers” to withstand pathogens.When exposed to S.Typhimurium,autophagy serves as the first barrier of immune defense to eliminate S.Typhimurium.When iron is overloaded,the first barrier of autophagy is closed and the the second barrier of nutritional immunity is turned on.Nutritional immunity mediated by Ferritin inhibits the proliferation and invasion of S.Typhimurium.This study thus reveals a novel,conserved signal pathway in C.elegans and mammalian cells,namely the Ferritin mediated nutritional immune signaling pathway in the intestinal epithelial cells,thereby laying a molecular foundation for the prevention and treatment of intestinal infectious diseases in the future. |
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