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Updated: Jun 14, 2025
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
FOS+ Macrophages Promote Chronic Rejection of Cardiac Transplantation
Shi Chen1, Wang Yi, Huisheng Zhou
1>From the Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China Key Laboratory of Organ Transplantation, Ministry of Education; the NHC Key Laboratory of Organ Transplantation; and the Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
Insights
CD40 signaling in macrophages promotes chronic transplant rejection by upregulating FOS family members. Inhibiting this pathway reduces graft fibrosis and improves survival.
Area of Science:
- Immunology
- Transplantation Biology
Background:
- Chronic rejection is a major cause of graft failure.
- Macrophages and CD40 signaling are implicated in chronic rejection.
- The role of FOS family members in this process is not fully understood.
Purpose of the Study:
- To investigate the role of FOS-positive macrophages regulated by CD40 in chronic allograft rejection.
- To elucidate the underlying mechanisms of CD40-mediated FOS family member regulation.
Main Methods:
- Analysis of single-cell sequencing data from kidney transplant recipients.
- Establishment of a chronic rejection mouse model.
- Assessment of FOS family expression using various techniques (flow cytometry, qPCR, Western blotting, immunofluorescence).
- RNA sequencing and ChIP-sequencing to identify signaling pathways and transcription factor binding.
Main Results:
- FOS was highly expressed on CD40hi macrophages in chronic transplant rejection.
- CD40 activation of NF-κB2 upregulates c-Fos and FosB, promoting cardiac transplant rejection.
- NF-κB2 binds to c-fos and fosb promoter regions.
- Inhibition of c-Fos/activator protein-1 reduced graft fibrosis and prolonged survival.
Conclusions:
- CD40-activated NF-κB2 in macrophages upregulates c-Fos and FosB, contributing to chronic transplant rejection.
- Targeting c-Fos/activator protein-1 may be a therapeutic strategy to reduce graft fibrosis and improve transplant outcomes.
Objectives:
Chronic rejection remains the leading cause of progressive decline in graft function. Accumulating evidence indicates that macrophages participate in chronic rejection dependent on CD40-CD40L. The FOS family members are critical in inflammatory and immune responses. However, the mechanisms underlying the role of FOS family members in chronic rejection remain unclear. In this study, we aimed to elucidate the role and underlying mechanisms of FOS-positive macrophages regulated by CD40 that mediate chronic allograft rejection.
Materials And Methods:
We downloaded publicly accessible chronic rejection kidney transplant single-cell sequencing datasets from the gene expression omnibus database. Differentially expressed genes between the CD40hi and CD40low macrophage chronic rejection groups were analyzed. We established a chronic rejection mouse model by using CTLA-4-Ig. We treated bone marrow-derived macrophages with an anti-CD40 antibody. We assessed expression of the FOS family by flow cytometry, real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. We identified altered signaling pathways by using RNA sequencing analysis. We detected DNA specifically bound to transcription factors by using ChIP-sequencing, with detection of the degree of graft fibrosis and survival.
Results:
FOS was highly expressed on CD40hi macrophages in patients with chronic transplantrejection. Mechanistically, we showed that CD40 activated NF-κB2 translocation into the nucleus to upregulate c-Fos and FosB expression, thus promoting chronic rejection of cardiac transplant.We showed thatNF-κB2 regulated c-Fos and FosB expression by binding to the c-fos and fosb promoter regions. Inhibition of c-Fos/activator protein-1 decreased graft fibrosis and prolonged graft survival.
Conclusions:
CD40 may activate transcription factor NF-κB2 translocation into the nucleus of macrophages to upregulate c-Fos and FosB expression, thus promoting chronic rejection of cardiac transplant. Inhibition of c-Fos/activator protein-1 decreased grafts fibrosis and prolonged graft survival.
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