Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune-cell checkpoint receptor/ligand pair PD-1/PD-L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD-L1 and PD-1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD-L1 from astrocytes, which may mediate ectodomain signaling to PD-1-expressing microglia. Deletion of microglial PD-1 evoked an inflammatory response and compromised amyloid-β peptide (Aβ) uptake. APP/PS1 mice deficient for PD-1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD-1/PD-L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD.

Introduction:The regulation of CD274 (PD-L1), a pivotal immune checkpoint in cancer immunotherapy, remain incompletely understood. The male-specific lethal (MSL) complex, initially identified in dosage compensation, contains the core subunit KAT8 (MOF), which catalyzes histone H4 lysine 16 acetylation (H4K16ac). However, whether the MSL complex directly regulates CD274 transcription has not been established. Methods:Using TIMER and GEPIA2, we charted pan-cancer expression of MSL subunits and their correlation with immune infiltration, integrating Kaplan-Meier survival and copy number variation (CNV) data to assess clinical relevance. CRISPR-Cas9 deletion of MSL1 or MSL3 in HEK293T cells, followed by RNA-seq, identified CD274 as a potential target. MSL1 knockdown or overexpression in LNCaP, HCT116, HeLa and MCF-7 cells confirmed regulation of CD274 protein, validated by rescue experiments in HEK293T cells. Luciferase reporter, ChIP-qPCR and ChIP-seq analyses collectively map the MSL-complex-CD274 regulatory axis. Results and discussion:Here we demonstrate that MSL1, a key subunit of the complex directly activates CD274 transcription by recruiting MOF to its promoter region and promoting H4K16 acetylation. Bioinformatic analyses revealed strong correlations between MSL1 expression, immune cell infiltration, and enrichment of immune-related gene sets across multiple cancer types. CRISPR/Cas9-mediated knockout of MSL1 or MSL3 markedly suppressed CD274 expression, whereas MSL1 overexpression enhanced CD274 levels and upregulated downstream immune- and apoptosis-related genes, including and . Dual-luciferase reporter assays, ChIP-qPCR and ChIP-seq further confirmed MSL1 binding near the -700 bp region of the CD274 promoter. Collectively, these findings uncover a previously unrecognized epigenetic mechanism linking the MSL complex to CD274 transcriptional regulation and identify MSL1 as a potential target for enhancing immunotherapy efficacy.