Interstitial macrophages drive chronic lung allograft dysfunction

Suzuki, A.; Schleck, M. J.; Wu, Q.; Fenton, R. A.; Cusick, L.; Kaiho, T.; Abdala-Valencia, H.; Yu, Z.; Sokolenko, Y. V.; Lu, Z.; Swaminathan, S.; Carns, M.; Mohsin, S.; Cooper, P.; Mehta, V.; Nagano, T.; Cooper, L. A. D.; Venkata Subramani, M.; Myers, C. N.; Arunachalam, A.; Kurihara, C.; Bharat, A.; Budinger, G. R. S.; Misharin, A. V.

doi:10.64898/2026.08.21.746267

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bioRxiv · 10.64898/2026.08.21.746267

Interstitial macrophages drive chronic lung allograft dysfunction

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Abstract

Despite immunosuppressive regimens targeting adaptive immunity, chronic lung allograft dysfunction (CLAD) remains the major obstacle to durable lung allograft survival. Here, we identify colony-stimulating factor 1 receptor (CSF1R)-expressing interstitial macrophages as critical orchestrators of CLAD. Using lung tissue from patients with CLAD and a mouse model of mismatched lung transplantation, we show that both donor-derived tissue-resident and recipient- monocyte-derived interstitial macrophages spatially co-localize within peribronchial immune aggregates in patients with CLAD. These interstitial macrophages express distinct cytokine programs that include those implicated in the recruitment of T and B cells. Pharmacological inhibition of CSF1R after lung transplantation in mice reduced interstitial macrophage abundance and attenuated CLAD pathology. Our findings identify donor- and recipient-derived interstitial macrophages as upstream regulators of CLAD and suggest CSF1R as a therapeutic target for its prevention and treatment.

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Suzuki, A., Schleck, M. J., Wu, Q., Fenton, R. A., Cusick, L., Kaiho, T., Abdala-Valencia, H., Yu, Z., Sokolenko, Y. V., Lu, Z., Swaminathan, S., Carns, M., Mohsin, S., Cooper, P., Mehta, V., Nagano, T., Cooper, L. A. D., Venkata Subramani, M., Myers, C. N., Arunachalam, A., Kurihara, C., Bharat, A., Budinger, G. R. S., Misharin, A. V.. 2026-08-25. Interstitial macrophages drive chronic lung allograft dysfunction. https://doi.org/10.64898/2026.08.21.746267

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