Related Experiment Video
Updated: May 27, 2025
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
CD40 induces PIR-A+ macrophages to promote chronic allograft rejection
Shi Chen1, Yuanyuan Zhao2, Wang Yi2
1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; Department of Thyroid Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Background:
Chronic rejection is the leading cause of progressive allograft function decline. Studies have demonstrated that CD40-CD40L-induced paired immunoglobulin-like receptor-A (PIR-A) is the MHC-I receptor necessary for the specific memory response in macrophages of mice with chronic rejection. However, the underlying mechanisms remain unclear.
Methods:
BALB/c mouse hearts were transplanted into C57BL/6, RelB-/- or LysMCrePirafl/fl mice, and a chronic rejection model was established by injecting CTLA-4-Ig. CD40-CD40L blockade in recipients by injecting anti-CD40L antibody. Allograft survival was monitored and histologically was assessed. Bone marrow-derived macrophages were treated with an anti-CD40 antibody. PIR-A expression was assessed via various methods in vivo and in vitro. Transcription factor expression levels were detected using RNA sequencing. DNA specifically bound to transcription factors was detected using ChIP-seq.
Results:
CD40 and PIR-A were highly expressed and colocalized in macrophage-infiltrating allograft in the mouse model. CD40-CD40L blockade inhibited PIR-A expression and prolonged allograft survival. Conditional deletion of Pira in recipient's macrophages inhibited chronic rejection and promoted long-term allograft acceptance. Mechanistically, CD40 may activate transcription factor NF-κB2 translocation into the nucleus to up-regulate PIR-A expression, promoting chronic rejection of cardiac transplantation. NF-κB2 regulated PIR-A expression by binding to the intergenic region of Pira.
Conclusions:
Our data suggest that Pira is a potential target to induce long-term allograft tolerance. CD40 may activate transcription factor NF-κB2 translocation into the nucleus to up-regulate PIR-A expression, promoting chronic rejection of cardiac transplantation. The study findings provide novel therapeutic opportunities to promote transplant survival in clinical settings.
