Annexin A2 regulates unfolded protein response via IRE1–XBP1 axis in macrophages during P. aeruginosa infection

Pseudomonas aeruginosa is a severe Gram‐negative opportunistic bacterium that causes a spectrum of organ system diseases, particularly in immunocompromised patients. This bacterium has been shown to induce unfolded protein response (UPR) during mammalian infection. Annexin A2 (AnxA2) is a multicompartmental protein relating to a number of cellular processes; however, it remains unknown whether AnxA2 coordinates a UPR pathway under bacterial infection conditions. Here, we report that the endoplasmic reticulum stress inositol‐requiring enzyme 1 (IRE1)–X‐box binding protein 1 (XBP1) pathway was up‐regulated by AnxA2 through p38 MAPK signaling following P. aeruginosa infection in macrophages, whereas ATF4 and ATF6 not. In addition, XBP1 was found as a positive regulator of innate immunity to tame P. aeruginosa challenges by enhancing autophagy and bacterial clearance. XBP1 also facilitated NF‐κB activation to elicit the release of proinflammatory cytokines predominantly in macrophages. Together, our findings identify AnxA2 as a regulator for XBP1‐mediated UPR pathway.