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Summary  Neutrophil (polymorphonuclear leucocytes;  PMN ) transmigration across mucosal surfaces contributes to dysfunction of epithelial barrier properties, a characteristic underlying many mucosal inflammatory diseases. Using   S   almonella  enterica serovar  T yphimurium (  S  .  T yphimurium) as a prototypic proinflammatory insult, we have previously reported that the eicosanoid hepoxilin  A  3  ( HXA 3  ), an endogenous product of 12‐lipoxygenase (12‐ LOX ) activity, is secreted from the apical surface of the intestinal epithelium to establish a chemotactic gradient that guides  PMN  across the epithelial surface. Since little is known regarding the molecular mechanisms that regulate 12‐ LOX  during   S  .  T yphimurium infection, we investigated this pathway. We found that expression of phospholipid glutathione peroxidase ( GPX4 ), which is known to have an inhibitory effect on 12‐ LOX  activity, is significantly decreased at both the  mRNA  and protein level during infection with   S  . Typhimurium. Moreover, employing intestinal epithelial cell monolayers expressing  siRNA  against  GPX4 mRNA ,   S  .  T yphimurium‐induced  PMN  migration was significantly increased compared with the non‐specific  siRNA  control cells. Conversely, in cells engineered to overexpress  GPX4 ,   S  .  T yphimurium‐induced  PMN  migration was significantly decreased, which is consistent with the finding that partial depletion of  GPX4  by  RNAi  resulted in a significant increase in  HXA 3   secretion during   S  .  T yphimurium infection. Mechanistically, although we found   S   almonella  entry not to be required for the induced decrease in  GPX4 , the secreted effector,  SipA , which is known to induce epithelial responses leading to stimulation of  HXA 3  , governed the decrease in  GPX4  in a process that does not lead to an overall increase in the levels of  ROS . Taken together, these results suggest that   S  .  T yphimurium induces apical secretion of  HXA 3   by decreasing the expression of phospholipid  GPX , which in turn leads to an increase in 12‐ LOX  activity, and hence  HXA  3  synthesis.

The oxido‐reductase enzyme glutathione peroxidase 4 ( GPX4 ) governs S almonella T yphimurium‐induced neutrophil transepithelial migration