Zusammenfassung
The innate receptor triggering-receptor-expressed-on-myeloid-cells-1 (TREM-1) enhances downstream signaling of pattern recognition receptor (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM-1+ antigen-presenting cells (APC) on alloreactive CD4+ lymphocytes. Bm12 donor ...
Zusammenfassung
The innate receptor triggering-receptor-expressed-on-myeloid-cells-1 (TREM-1) enhances downstream signaling of pattern recognition receptor (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM-1+ antigen-presenting cells (APC) on alloreactive CD4+ lymphocytes. Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12-donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM-1+CD11b+MHC-II+F4/80+CCR2+ APC and IFN-producing CD4+ cells were detected during chronic rejection. Peptide inhibition of TREM-1 attenuated graft vasculopathy, reduced graft-infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4+ and CD8+ cell infiltration. Remarkably, temporary inhibition of TREM-1 during early immune activation was sufficient for long-term allograft survival. Mechanistically, TREM-1 inhibition leads to reduced differentiation and proliferation of IFN-producing Th1 cells. In conclusion, TREM-1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4+ lymphocytes.
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