Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na⁺ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca²⁺ influx that leads to prostaglandin E₂ (PGE₂) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE₂ production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.

The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in β-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca2+ oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse β-cells or RINm5F β-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 β-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in β-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy.

Stroke induces rapid activation and expansion of microglia, but the main source of microgliosis is controversial. Here we investigated the formation of microgliosis and infiltration of circulating cells in a photothrombosis stroke model by taking advantage of parabiosis and two-photon microscopy. We found that a small population of blood-derived CX3CR1(GFP/+) cells infiltrated the cerebral parenchyma, but these cells did not proliferate and were phenotypically distinguishable from resident microglia. CX3CR1(GFP/+) infiltrating cells also displayed different kinetics from reactive microglia. The number of CX3CR1(GFP/+) infiltrating cells peaked on Day 5 after stroke and then decreased. The decline of these infiltrating cells was associated with an active apoptotic process. In contrast, reactive microglia were recruited to the ischaemic area continuously during the first week after stroke induction. Immunohistology and in vivo two-photon imaging revealed that cells involved in the process of microgliosis were mainly derived from proliferating resident microglia. Expansion of microglia exhibited a consistent pattern and our in vivo data demonstrated for the first time that microglia underwent active division in regions surrounding the ischaemic core. Together, these results indicated that CX3CR1(GFP/+) infiltrating cells and reactive microglia represented two distinct populations of cells with different functions and therapeutic potentials for the treatment of stroke.

Here we find that CD8 + T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49 + CD8 + regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8 + T cells efficiently eliminated pathogenic gliadin-specific CD4 + T cells from celiac disease patients’ leukocytes in vitro. We also find elevated levels of KIR + CD8 + T cells, but not CD4 + regulatory T cells, in COVID-19 patients, which correlated with disease severity and vasculitis. Selective ablation of Ly49 + CD8 + T cells in virus-infected mice led to autoimmunity post infection. Our results indicate that in both species, these regulatory CD8 + T cells act uniquely to suppress pathogenic T cells in autoimmune and infectious diseases.

Immune checkpoint-blocking antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe immune-related adverse events. Previously, we found that Bifidobacterium could mitigate intestinal immunopathology in the context of CTLA-4 blockade in mice. Here we examined the mechanism underlying this process. We found that Bifidobacterium altered the composition of the gut microbiota systematically in a regulatory T cell (Treg)-dependent manner. Moreover, this altered commensal community enhanced both the mitochondrial fitness and the IL-10–mediated suppressive functions of intestinal Tregs, contributing to the amelioration of colitis during immune checkpoint blockade.