Single-cell and spatial profiling of peripheral blood and synovium unveils pro-arthritis CNBP+ myeloid cells

BACKGROUND: Arthritis ranks as a primary contributor to global disability, with synovitis representing a common pathological feature across all types of arthritis. Given that macrophages constitute the predominant inflammatory cells in arthritic synovium, deciphering their heterogeneity facilitates the elucidation of pathogenic mechanisms. METHODS: We integrated single-cell transcriptomic profiles from human peripheral blood and synovial tissue across 173 samples encompassing six types of arthritis to characterize transcriptional remodeling, including molecular signatures, transcriptional regulation, tissue distribution, and cellular interactions. Immunofluorescence staining and spatial transcriptomic analyses were performed to substantiate the proposed mechanism. RESULTS: We identified an expanded population of peripheral CCHC-type zinc finger nucleic acid binding protein (CNBP)+ monocytes exhibiting elevated scores of the “inflammatory response” pathway in arthritis patients. Synovial CNBP+ macrophages presented the highest peripheral CNBP+ monocyte signature scores. Independent single-cell and bulk transcriptomic data revealed increased expression of CNBP+ macrophage signatures in both human and mice arthritis samples. CNBP+ macrophage signature scores were positively associated with inflammatory scores, as validated by immunofluorescence staining. Abundances of CD56+ CD16− natural killer (NK) cells and CNBP+ macrophages were positively correlated. Multiplex immunofluorescence staining from a limited number of synovial samples, together with spatial transcriptomic analyses suggested potential communication between CD56+ CD16− NK cells and CNBP+ macrophages via ANXA1–FPR3 axis. Furthermore, CNBP+ macrophages highly expressed MHC class II molecules and interacted with interferon-high CD4+ T cells through CD86 signaling. CONCLUSIONS: Our findings highlight the immune crosstalk involving CNBP+ macrophages in arthritis and enlighten treatment development targeting NK-macrophage-T axis.