MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of ischemia/reperfusion injury after lung transplant
Victoria Leroy, … , Gilbert R. Upchurch Jr., Ashish K. Sharma
Victoria Leroy, … , Gilbert R. Upchurch Jr., Ashish K. Sharma
Published August 22, 2024
Citation Information: JCI Insight. 2024;9(19):e179876. https://doi.org/10.1172/jci.insight.179876.
View: Text | PDF
Research Article Immunology Transplantation

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of ischemia/reperfusion injury after lung transplant

Abstract

Lung transplantation (LTx) outcomes are impeded by ischemia/reperfusion injury (IRI) and subsequent chronic lung allograft dysfunction (CLAD). We examined the undefined role of receptor Mer tyrosine kinase (MerTK) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis to facilitate resolution of lung IRI. Single-cell RNA sequencing of lung tissue and bronchoalveolar lavage (BAL) from patients after LTx were analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with BALB/c (WT), Cebpb–/– (MDSC-deficient), Mertk–/–, or MerTK–cleavage-resistant mice. A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of patients with CLAD was observed compared with healthy individuals. In the murine IRI model, a significant increase in M-MDSCs, MerTK expression, and efferocytosis and attenuation of lung dysfunction was observed in WT mice during injury resolution that was absent in Cebpb–/– and Mertk–/– mice. Adoptive transfer of M-MDSCs in Cebpb–/– mice significantly attenuated lung dysfunction and inflammation. Additionally, in a murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. Our results suggest that MerTK-dependent efferocytosis by M-MDSCs can substantially contribute to the resolution of post-LTx IRI.

Authors

Victoria Leroy, Denny J. Manual Kollareth, Zhenxiao Tu, Jeff Arni C. Valisno, Makena Woolet-Stockton, Biplab Saha, Amir M. Emtiazjoo, Mindaugas Rackauskas, Lyle L. Moldawer, Philip A. Efron, Guoshuai Cai, Carl Atkinson, Gilbert R. Upchurch Jr., Ashish K. Sharma

×

Figure 8

Resolution of IRI in an allogeneic orthotopic brain-dead model of IRI after LTx is associated with increase in M-MDSCs.

Options: View larger image (or click on image) Download as PowerPoint
Resolution of IRI in an allogeneic orthotopic brain-dead model of IRI af...
(A) Schematic depicting brain-dead model of LTx in C57BL/6 donors and WT (BALB/c) recipients. (B and C) Representative flow cytometry plots and quantification of M-MDSCs in lung tissue from LTx recipients. The percentage of M-MDSCs was significantly upregulated after 72 hours of reperfusion to 24 hours. *P = 0.03 vs. 24 hours; n = 5–6/group. (D) Albumin levels in BAL were significantly mitigated following 72 hours of reperfusion compared with 24 hours of reperfusion. *P = 0.0079; n = 5/group. (E–G) Expression of pro-inflammatory cytokines in BAL was significantly mitigated and IL-10 expression was significantly increased after 72 hours compared with 24 hours of reperfusion. *P < 0.04; n = 5/group. (H and I) PMN infiltration in lung tissue was significantly abrogated following 72 hours of reperfusion compared with 24 hours. *P = 0.01; n = 4–5/group. Scale bars represent 100 μm. (J) MPO expression in BAL was significantly mitigated following 72 hours of reperfusion. *P = 0.0079; n = 5/group. (K) sol-MER levels in BAL were significantly decreased in LTx recipient mice following 72 hours of reperfusion compared with 24 hours. *P = 0.016; n = 5/group. Data analyzed by Mann-Whitney test.