Paradoxical Expression of Ionotropic Glutamate Receptors in Leucocytes.

UNLABELLED: The expression of the ionotropic glutamate receptors AMPAR and NMDAR has been measured on circulating leucocytes, particularly CD4+ lymphocytes, in many studies over the last two decades. As there are agonists and antagonists for these receptors that do not cross the blood brain barrier, they represent potential new avenues to target leucocytes in human disease. To determine the range of expression across pathological conditions, we compared the expression of AMPAR and NMDAR, as well as kainate receptors and metabotropic receptors, in 12 clinical studies including inflammatory autoimmune disease (rheumatoid arthritis, juvenile idiopathic arthritis, lupus and multiple sclerosis), breast cancer, viral infection, schizophrenia and in vitro studies. We measured the expression of AMPAR and NMDAR in freshly isolated CD4+ T cells, stimulated PBMC and myeloid cells (HL-60, THP-1 and monocyte-derived macrophages) using TaqMan qPCR. We found the gene expression of glutamate receptors to be negligible with few exceptions. We measured low but reproducible expression of GRIA3 in THP-1 pro-monocytic cells and human blood dendritic cell subsets (pDC, cDC1, cDC2). We observed that AMPA pre-treatment caused a greater inflammatory response in TNF-stimulated THP-1 cells. While these data illustrate a contradiction in the literature, the limited but reproducible expression of glutamate receptors in select immune subsets potentiates peripheral therapeutic targeting in specific disease contexts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12016-025-09126-2.