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

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Figure 6

M-MDSC–mediated resolution of lung IRI is mediated via MerTK.

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M-MDSC–mediated resolution of lung IRI is mediated via MerTK. (A) Schema...
(A) Schematic depicting adoptive transfer of M-MDSCs prior to IRI (24 hours) in Cebpb–/– mice. (B–D) Treatment with M-MDSCs from WT mice, but not from Mertk–/– mice, significantly mitigated lung dysfunction compared with untreated mice. *P < 0.006 vs. other groups; n = 7–10/group. (E–G) Expression of pro-inflammatory cytokines was significantly decreased in mice treated with WT M-MDSCs but not with Mertk–/– M-MDSCs. *P < 0.05 vs. IRI; #P < 0.05 vs. IRI+WT M-MDSCs; n = 6–8/group. (H and I) PMN infiltration was significantly attenuated by treatment with WT-derived M-MDSCs but not Mertk–/–-derived M-MDSCs. *P < 0.0001 vs. IRI; #P = 0.0005 vs. IRI+WT M-MDSCs; n = 5–7/group. Scale bars represent 100 μm. (J) MPO levels in BAL were significantly mitigated by WT M-MDSCs but not by Mertk–/– M-MDSCs. *P < 0.05 vs. IRI alone; #P < 0.05 vs. IRI + WT M-MDSCs; n = 5–7/group. Data analyzed by 1-way ANOVA and Tukey’s multiple comparisons test.