The variegated expression of the KIR family of class I MHC receptors generates specialized natural killer (NK) cells capable of allele-specific HLA recognition. Understanding the mechanism of KIR gene activation will lead to improved methods for the generation of fully functional NK cells. A central RUNX-binding site in the KIR proximal promoter is required for gene activation. RUNX proteins recruit ten-eleven translocation (TET) proteins that generate 5-hydroxymethylcytosine (5hmC) and drive DNA demethylation. Assessment of 5-methylcytosine (5mC) and 5hmC residues at four stages of NK cell development reveals deposition of 5hmC primarily in a CREB site next to the RUNX site at the CD56Bright stage but not the subsequent CD56Dim stage representing fully mature NK cells. KIR promoter demethylation is delayed relative to other lineage-associated genes, indicating a high threshold for KIR gene demethylation in developing NK cells, and a window of opportunity for RUNX/TET-dependent KIR gene activation in CD56Bright NK cells.

Disruption of liver metabolism alters immune responses, with maximal immune activation occurring when metabolic stress increases bone marrow hematopoietic stem cell (HSC) activity. We previously showed that sustained HSC activation enhances liver immune surveillance and reduces tumor burden. In the present study, we show that short-term HSC stimulation alone is insufficient for tumor control. Dietary supplementation with cholesterol and cholic acid, however, synergistically stimulates HSC responses and markedly elevates serum taurocholic acid (T-CA). Pharmacological inhibition of the apical sodium-dependent bile acid transporter (ASBT) restores bile acid homeostasis and lowers circulating T-CA, attenuating HSC activation and liver inflammation. Collectively, these findings reveal a bile acid-mediated liver-bone marrow crosstalk with direct implications for metabolic and neoplastic liver diseases.

ObjectiveThis study investigated how cumulative environmental exposures influence offspring behaviour and inflammation-related molecular signatures in the brain and peripheral immune system.MethodsA novel "triple-hit" mouse model was developed using C57Bl/6JAusB mice (N = 70), combining preconceptual social stress, antenatal high-fat diet, and a postnatal immune challenge (poly(I:C), 10 mg/kg). At 12 weeks, offspring underwent behavioural tests relevant to neurodevelopmental disorders (NDDs), including the Elevated Plus Maze, 3-Chamber Social Preference, Self-Grooming, and Marble Burying. A composite NDD-risk index was calculated. Single-cell RNA sequencing (scRNA-seq) and bulk proteomics were performed on male triple-hit offspring to identify differentially expressed genes and proteins associated with inflammatory pathways.ResultsMale triple-hit offspring showed elevated NDD-related behavioural risk and social deficits, not observed in females. scRNA-seq revealed altered inflammatory and ribosomal pathways in brain glia and peripheral immune cells. Proteomic analysis showed decreased abundance of proteins involved in inflammation, translation, chromatin remodelling, and synaptic function in both brain and blood.ConclusionCombined environmental stressors may drive male-specific behavioural and inflammatory changes relevant to NDDs. The identification of overlapping inflammatory signatures in brain and peripheral immune cells supports a role for shared immune mechanisms in brain–immune axis dysfunction. However, these pathway-level findings should be interpreted as preliminary hypotheses and warrant independent validation to confirm their mechanistic significance.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00011-025-02152-y.