ABSTRACT
Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45+ cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1Bhi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1Bhi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1Bhi monocytes. Exhausted CD8+ T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1Bhi myeloid cells communicated with CD8+ Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1Bhi macrophages as a possible therapeutic target in PD-1-IA.
Subject(s)
Arthritis, Rheumatoid , Immune Checkpoint Inhibitors , Humans , CD8-Positive T-Lymphocytes/metabolism , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/metabolism , Inflammation/metabolism , Macrophages/metabolism , Synovial Fluid , Interleukin-1beta/genetics , Interleukin-1beta/metabolismABSTRACT
Visualization of the cerebral vascular tree is important in experimental stroke and cerebral vascular malformation research. We describe a simple method, nuclear contrast angiography, that enables simultaneous visualization of the arterial tree and cerebral endothelial cells in rodent brain whole mounts. A mixture of latex and black ink was injected into the arterial system of rodents, resulting in high contrast demarcation of the arterial tree of the brain. This method clearly differentiates arteries from veins. We applied this method to demonstrate that 14 days of unilateral carotid artery occlusion induces increases in the caliber of (1) bilateral anterior communicating arteries, (2) bilateral anterior cerebral arteries, and (3) ipsilateral proximal middle cerebral artery of the circle of Willis. Unlike other methods, this procedure selectively stains endothelial nuclei of arteries. Thus, cerebral endothelial nuclei can be visualized, quantitated, and morphologically characterized at the same time the cortical arterial tree is delineated. This method should be useful in studies of stroke and cerebral arteriogenesis, which require the accurate assessment of both arterial diameters and endothelial cell density.
