TY  - JOUR
AU  - Kummer, Markus P.
AU  - Ising, Christina
AU  - Kummer, Christiane
AU  - Sarlus, Heela
AU  - Griep, Angelika
AU  - Vieira-Saecker, Ana
AU  - Schwartz, Stephanie
AU  - Halle, Annett
AU  - Brückner, Matthias
AU  - Händler, Kristian
AU  - Schultze, Joachim L
AU  - Beyer, Marc-Daniel
AU  - Latz, Eicke
AU  - Heneka, Michael
TI  - Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer's disease pathology.
JO  - The EMBO journal
VL  - 40
IS  - 24
SN  - 1460-2075
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-00156
SP  - e108662
PY  - 2021
AB  - 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.
KW  - Aged
KW  - Aged, 80 and over
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: immunology
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: toxicity
KW  - Animals
KW  - Astrocytes: metabolism
KW  - B7-H1 Antigen: metabolism
KW  - CD36 Antigens: metabolism
KW  - Case-Control Studies
KW  - Disease Models, Animal
KW  - Female
KW  - Gene Deletion
KW  - HEK293 Cells
KW  - HeLa Cells
KW  - Humans
KW  - Male
KW  - Mice
KW  - Mice, Transgenic
KW  - Microglia: metabolism
KW  - Middle Aged
KW  - Programmed Cell Death 1 Receptor: genetics
KW  - Programmed Cell Death 1 Receptor: metabolism
KW  - Up-Regulation
KW  - APP (Other)
KW  - PD-1 knockout mice (Other)
KW  - PS1 mice (Other)
KW  - innate immune system (Other)
KW  - microglia (Other)
KW  - APP protein, human (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - B7-H1 Antigen (NLM Chemicals)
KW  - CD274 protein, human (NLM Chemicals)
KW  - CD36 Antigens (NLM Chemicals)
KW  - CD36 protein, human (NLM Chemicals)
KW  - PDCD1 protein, human (NLM Chemicals)
KW  - Programmed Cell Death 1 Receptor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34825707
C2  - pmc:PMC8672180
DO  - DOI:10.15252/embj.2021108662
UR  - https://pub.dzne.de/record/163394
ER  -