Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis

• Published in: Atherosclerosis 2022-07, Vol.352, p.1-9
• Main Authors: Douna, Hidde, Smit, Virginia, van Puijvelde, Gijs H.M., Kiss, Mate G., Binder, Christoph J., Bot, llze, Kuchroo, Vijay K., Lichtman, Andrew H., Kuiper, Johan, Foks, Amanda C.
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Cardiovascular disease; Immunity; Inflammation; Tim-1
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2022.05.017

Increasing evidence has shown that immune checkpoint molecules of the T-cell immunoglobulin and mucin domain (Tim) family are associated with diverse physiologic and pathologic processes. Previous studies of the role of Tim-1 in atherosclerosis using anti-Tim-1 antibodies have yielded contradictory results. We thus aimed to investigate atherosclerosis development in Tim-1 deficient mice. Mice with a specific loss of the Tim-1 mucin-domain (Tim-1Δmucin) and C57BL/6 (WT) mice received a single injection of a recombinant adeno-associated virus encoding murine Pcsk9 (rAAV2/8-D377Y-mPcsk9) and were fed a Western type diet for 13 weeks to introduce atherosclerosis. Tim-1Δmucin mice developed significantly larger lesions in the aortic root compared to WT mice, with significantly more macrophages and a trend towards a larger necrotic core. Furthermore, Tim-1Δmucin mice showed a significant loss of IL-10+ B cells and regulatory B cell subsets and increased pro-atherogenic splenic follicular B cells compared to WT mice. Moreover, Tim-1Δmucin mice displayed a dramatic reduction in Th2-associated immune response compared to controls but we did not observe any changes in humoral immunity. In summary, Tim-1Δmucin mice displayed a profound impairment in IL-10+ B cells and an imbalance in the Th1/Th2 ratio, which associated with exacerbated atherosclerosis. [Display omitted] •TIm-1 deficient mice show exacerbated atherosclerosis.•Regulatory IL-10+ B cells are reduced in atherosclerotic TIm-1 deficient mice.•Atherosclerotic TIm-1 deficient mice show increased follicular B cells and an imbalanced Th1/Th2 ratio.•Despite reduced Th2-associated immunity, humoral responses are unaffected.