Chronic non-healing wounds are a major complication of diabetes, which impacts 1 in 10 people worldwide. Dying cells in the wound perpetuate the inflammation and contribute to dysregulated tissue repair 1-3 . Here, we reveal the membrane transporter Slc7a11 as a molecular 'brake' on efferocytosis, the process by which dying cells are removed, and that inhibiting Slc7a11 can accelerate wound healing. First, transcriptomics of efferocytic dendritic cells identified upregulation of several Slc7 gene family members. In further analyses, pharmacological inhibition, siRNA knockdown, or deletion of Slc7a11 enhanced dendritic cell efferocytosis. Interestingly, Slc7a11 was highly expressed in skin dendritic cells, and scRNAseq of inflamed skin showed Slc7a11 upregulation in innate immune cells. In a mouse model of excisional skin wounding, loss of Slc7a11 expression or inhibition accelerated healing dynamics and reduced apoptotic cell load in the wound. Mechanistic studies revealed a link between Slc7a11, glucose homeostasis, and diabetes. Slc7a11-deficient dendritic cells relied on glycogen store-derived aerobic glycolysis for improved efferocytosis, and transcriptomics of efferocytic Slc7a11-deficient dendritic cells identified genes linked to gluconeogenesis and diabetes. Further, Slc7a11 expression was higher in the wounds of diabetic-prone db/db mice, and targeting Slc7a11 accelerated their wound healing. The faster healing was also linked to the release of TGF- family member GDF15 from efferocytic dendritic cells. Collectively, Slc7a11 is a negative regulator of efferocytosis, and removing this brake improves wound healing, with significant implications for diabetic wound management.

Activated invariant natural killer T (iNKT) cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear. Here we show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), links key cellular processes required for iNKT cell effector functions in specific iNKT subsets, in which TCR-dependent activation of IRE1α is associated with downstream activation of p38 MAPK and the stabilization of preformed cytokine mRNAs. Importantly, genetic deletion of IRE1α in iNKT cells reduces cytokine production and protects mice from oxazolone colitis. We therefore propose that an IRE1α-dependent signaling cascade couples constitutive cytokine mRNA expression to the rapid induction of cytokine secretion and effector functions in activated iNKT cells.

No abstract