Identification and characterization of inflammatory LILR and fibrotic SPP1 macrophages in chronic lung allograft dysfunction

Chronic lung allograft dysfunction (CLAD) is a leading cause of death in lung transplant recipients, primarily presenting as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Despite the crucial role of pulmonary macrophages in lung injury and repair, their involvement in CLAD pathogenesis has been insufficiently explored.

A recent study employed single-cell RNA sequencing to analyze CLAD and control lung tissue samples, uncovering two primary macrophage populations: inflammatory macrophages expressing leukocyte immunoglobulin-like receptors (LILR) and fibrotic macrophages marked by osteopontin (SPP1) expression.

The inflammatory LILR macrophages were found in both BOS and RAS cases, while the fibrotic SPP1 macrophages were predominantly observed in RAS. Remarkably, these macrophage populations were also detected in idiopathic pulmonary fibrosis and cross-tissue comparisons, suggesting their relevance beyond CLAD. Through surface marker-based sorting techniques, researchers were able to isolate both macrophage subsets.

Functional analyses revealed that LILR macrophages displayed heightened phagocytic activity, facilitated T cell migration, and secreted inflammatory mediators. Conversely, SPP1 macrophages produced soluble factors that triggered fibroblast activation and contraction.

These findings significantly advance our understanding of CLAD pathogenesis by identifying distinct inflammatory and fibrotic macrophage programs. By linking RAS to conserved fibrotic macrophage states observed in pulmonary fibrosis, this study highlights the potential of targeting these macrophage populations as therapeutic strategies for inflammatory and fibrotic allograft injuries.