Increasing evidence implicates mitochondrial dysfunction in the pathogenesis of inflammatory bowel disease (IBD), with the IBD-associated pathobiont adherent-invasive E. coli-LF82 (AIEC) promoting epithelial mitochondrial depolarization and fragmentation and a concomitant reduction in barrier function. We hypothesized that the anti-inflammatory cytokine interleukin-10 (IL-10), essential for enteric homeostasis, would protect against AIEC-induced mitochondrial disruption. Mitochondrial fragmentation in colonic organoids following infection with E. coli-LF82 was reduced by IL-10 pretreatment + cotreatment. IL-10 significantly reduced the E. coli-LF82 induced mitochondrial dysfunction in the human colon-derived T84 epithelial cell line as measured by mitochondrial network analysis, membrane potential, permeability transition pore opening, oxidative phosphorylation (via oxygen consumption rate), and epithelial barrier integrity. IL-10-treated T84 cells and organoids exhibited increased phosphorylation of STAT3 at serine 727 (a requirement for STAT3 activity at mitochondria), which was abrogated by pharmacological inhibition of ERK (but not JAK) activation, leading to loss of protection against E. coli-LF82-induced mitochondrial dysfunction. Re-expression of wild-type STAT3, but not the S727A mutant, in HT-29 (human colon epithelial cell line) STAT3 knockout cells restored mitochondrial depolarization and ATP levels, underscoring the role of ERK-driven STAT3S727 phosphorylation in IL-10's protective mechanism. In contrast, IL-22, which primarily activates STAT3Y705 and not STAT3S727, failed to prevent AIEC-induced mitochondrial dysfunction. Thus, in the context of exposure to an E. coli pathobiont, IL-10 supports gut epithelial homeostasis via ERK-dependent STAT3S727 maintenance of mitochondrial integrity, contributing to preservation of epithelial barrier function.
Krishnan et al. (Thu,) studied this question.