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Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis
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 pro- cesses. Previous studies investigating 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.
In this study, mice with a specific loss of the TIM-1 mucin- domain
(TIM-1Dmucin) were used. TIM-1Dmucin mice and control WT (C57/
Bl6) mice received a single i.v. injection of 5x1011 rAAV8-D377Y-mPCSK9 vector genomes and were fed
a Western-type diet for 13 weeks.
TIM-1Dmucin mice developed significantly larger lesions in the
aortic root and arch compared to WT mice. These lesions were composed of significantly more
macrophages and showed a trend towards a ...
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 pro- cesses. Previous studies investigating 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.
In this study, mice with a specific loss of the TIM-1 mucin- domain
(TIM-1Dmucin) were used. TIM-1Dmucin mice and control WT (C57/
Bl6) mice received a single i.v. injection of 5x1011 rAAV8-D377Y-mPCSK9 vector genomes and were fed
a Western-type diet for 13 weeks.
TIM-1Dmucin mice developed significantly larger lesions in the
aortic root and arch compared to WT mice. These lesions were composed of significantly more
macrophages and showed a trend towards a larger necrotic core. The exacerbated
atherosclerosis in TIM-1Dmucin mice was associated with a significant loss of IL-10+ B cells
and regulatory B cell subsets compared to WT mice. TIM-1Dmucin mice also showed an increase in splenic and circulating leukocytes compared to WT mice, which was caused by an
increase in B and CD4+ T cells in the spleen, while no specific leukocyte population was
changed in the circulation. TIM- 1Dmucin mice also displayed a dramatic reduction in
Th2-associated immune response compared to controls but no changes in humoral immune response.
In summary, TIM-1Dmucin mice displayed a profound
impairment in IL-10+ B cells and an imbalance in the Th1/Th2 ratio, which
associated with exacerbated atherosclerosis.
- All authors
- Douna, H.; Smit, V.; Puijvelde, G. van; Binder, C.; Bot, I.; Kuchroo, V.; Lichtman, A.; Kuiper, J.; Foks, A.
- Date
- 2019-08-31
- Volume
- 287
- Pages
- E25 - E26