# Macrophages in Chronic Rejection: The Shapeshifters Behind Transplant Survival

## TL;DR

Macrophages, immune cells that can switch roles, play a key role in chronic rejection of transplanted organs and could be targeted to improve long-term transplant success.

## Contribution

This review highlights the dual and dynamic role of macrophages in chronic rejection and identifies therapeutic opportunities to reprogram them.

## Key findings

- Macrophages from both donor and recipient contribute to inflammation, vascular remodeling, and fibrosis in chronic rejection.
- Molecular pathways like NF-κB and inflammasomes drive macrophage polarization into destructive states.
- Targeting macrophages with drugs, gene therapy, or exosomes may reprogram them to preserve graft function.

## Abstract

Long-term survival of transplanted organs is limited by chronic rejection, a slow and progressive process that damages blood vessels and leads to loss of organ function. This review explains how macrophages, a type of immune cell with highly adaptable functions, play a central role in driving chronic rejection. Macrophages can originate from both the donor organ and the transplant recipient and can switch between inflammatory and tissue-repair programs in response to local signals. In chronic rejection, these cells often promote ongoing inflammation, vascular remodeling, and fibrosis. Understanding how macrophages contribute to chronic rejection may help guide the development of new therapies aimed at preserving transplanted organs and improving long-term transplant outcomes.

Background: Organ transplant offers patients a second chance at life, yet chronic rejection remains a formidable barrier to long-term success. Unlike the instantaneous storm of acute rejection, chronic rejection is a slow, unremitting process that silently remodels vessels, scars tissues, and diminishes graft function. At the center of this process are macrophages, immune “shapeshifters” that can heal or harm depending on their cues. Methods: This manuscript systematically reviews and synthesizes the current evidence from experimental studies and clinical observations, as well as molecular insights, to unravel how macrophages orchestrate chronic rejection. It travels over macrophage origins alongside their dynamic polarization into pro-inflammatory (M1) or pro-repair yet fibrotic (M2) states. The discussion integrates mechanisms of recruitment, antigen presentation, vascular injury, and fibrosis, while highlighting the molecular pathways (NF-κB, inflammasomes, STAT signaling, metabolic rewiring) that shape macrophage fate. Results: Macrophages play a central role in chronic rejection. Resident macrophages, once tissue peacekeepers, amplify inflammation, while recruited monocyte-derived macrophages fuel acute injury or dysfunctional repair. Together, they initiate transplant vasculopathy through cytokines, growth factors, and matrix metalloproteinases, slowly narrowing vessels and starving grafts. Donor-derived macrophages, often overlooked, act as early sentinels and long-term architects of fibrosis, blurring the line between donor and host immunity. At the molecular level, macrophages lock into destructive programs, perpetuating a cycle of inflammation, vascular remodeling, and scarring. Conclusions: Macrophages are not passive bystanders but pivotal decision makers in chronic rejection. Their plasticity, while a source of pathology, also opens therapeutic opportunities. Emerging strategies like macrophage-targeted drugs, immune tolerance approaches, gene and exosome therapies currently offer ways to reprogram these cells and preserve graft function. By shifting the macrophage narrative from saboteurs to guardians, transplantation medicine may transform chronic rejection from an inevitability into a preventable complication, extending graft survival from fleeting years into enduring decades.