Sphingosine 1‐phosphate elicits a ROS‐mediated proinflammatory response in human endometrial stromal cells via ERK5 activation

Endometriosis is a chronic gynecological disease affecting ~10% women in the reproductive age characterized by the growth of endometrial glands and stroma outside the uterine cavity. The inflammatory process has a key role in the initiation and progression of the disorder. Currently, there are no available early diagnostic tests and therapy relies exclusively on symptomatic drugs, so that elucidation of the complex molecular mechanisms involved in the pathogenesis of endometriosis is an unmet need. The signaling of the bioactive sphingolipid sphingosine 1‐phosphate (S1P) is deeply dysregulated in endometriosis. S1P modulates a variety of fundamental cellular processes, including inflammation, neo‐angiogenesis, and immune responses acting mainly as ligand of a family of G‐protein‐coupled receptors named S1P receptors (S1PR), S1P1–5. Here, we demonstrated that the mitogen‐activated protein kinase ERK5, that is expressed in endometriotic lesions as determined by quantitative PCR, is activated by S1P in human endometrial stromal cells. S1P‐induced ERK5 activation was shown to be triggered by S1P1/3 receptors via a SFK/MEK5‐dependent axis. S1P‐induced ERK5 activation was, in turn, responsible for the increase of reactive oxygen species and proinflammatory cytokine expression in human endometrial stromal cells. The present findings indicate that the S1P signaling, via ERK5 activation, supports a proinflammatory response in the endometrium and establish the rationale for the exploitation of innovative therapeutic targets for endometriosis.