Alveolar macrophage activation and polarization signatures in stable lung transplant recipients and chronic lung allograft dysfunction.

BACKGROUND

Long-term survival after lung transplantation (LTx) remains highly variable, with chronic lung allograft dysfunction (CLAD) as a major limiting factor. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) in more than 50% of LTx recipients. In contrast, a subgroup of "super survivors" maintains long-term graft stability for years without immunological complications. These patients show an increased prevalence of alveolar macrophages (AMs), but the mechanisms underlying stable graft function remain unclear.

METHODS

Transcriptome profiles of AMs were analyzed in lung tissues of super survivors (n = 15), recipients with BOS or RAS (n = 24), and healthy controls (n = 9) using spatial transcriptomics. AM origin was assessed in sex-mismatched cases (n = 8) using X/Y fluorescence in situ hybridization.

RESULTS

In super survivor AMs, upregulated genes were associated with stress control and detoxification (GSTA2, HBA2), innate immune regulation (INAVA), lipid homeostasis (APOE, CES1), and alveolar structure maintenance. Most AMs were donor-derived (61.3%). The majority (78.26%) displayed a pre-activated state with enhanced immune plasticity, while a smaller fraction (13.04%) showed M2-like repair functions. In BOS and RAS lungs, donor-derived AMs (37.4%) were largely replaced by recipient-derived cells. 35.71% of BOS and 56.52% of RAS AMs exhibited a progressive M1-like polarization. Transitional pre-BOS and pre-RAS stages suggested that early post-transplant conditions shape macrophage polarization and influence long-term outcomes.

CONCLUSIONS

Stable long-term graft function after LTx is associated with persistence of metabolically adapted donor-derived AMs, whereas CLAD reflects their replacement by inflammatory recipient cells. Preserving protective macrophage populations may help promote a long-term stable immune microenvironment after LTx.