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.
Show 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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