MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant injury

• Published in: bioRxiv
• Main Authors: Leroy, Victoria, Manual Kollareth, Denny J, Tu, Zhenxiao, Valisno, Jeff Arni C, Woolet-Stockton, Makena, Saha, Biplab, Emtiazjoo, Amir M, Rackauskas, Mindaugas, Moldawer, Lyle L, Efron, Philip A, Cai, Guoshuai, Atkinson, Carl, Upchurch, Gilbert R, Sharma, Ashish K
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 23.01.2024; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Adoptive transfer; Apoptosis; Down-regulation; Flow cytometry; Immunology; Inflammation; Ischemia; Leukocytes (neutrophilic); Lung diseases; Lung transplantation; Monocytes; Neutrophils; Peroxidase; Phagocytosis; Reperfusion; Respiratory function; Suppressor cells; Transplants & implants; Ischemia-reperfusion injury; monocytic-myeloid derived suppressor cells; MerTK; efferocytosis; transplantation
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.01.18.576261

Patients with end stage lung diseases require lung transplantation (LTx) that can be impeded by ischemia-reperfusion injury (IRI) leading to subsequent chronic lung allograft dysfunction (CLAD) and inadequate outcomes. We examined the undefined role of MerTK (receptor Mer tyrosine kinase) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis (phagocytosis of apoptotic cells) to facilitate resolution of lung IRI. Single-cell RNA sequencing of lung tissue and BAL from post-LTx patients was analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with Balb/c (WT), (MDSC-deficient), or MerTK-CR (cleavage resistant) mice. Lung function, IRI (inflammatory cytokine and myeloperoxidase expression, immunohistology for neutrophil infiltration), and flow cytometry of lung tissue for efferocytosis of apoptotic neutrophils were assessed in mice. A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients compared to healthy subjects was observed. In the murine IRI model, significant increase in M-MDSCs, MerTK expression and efferocytosis was observed in WT mice during resolution phase that was absent in Land mice. Adoptive transfer of M-MDSCs in mice significantly attenuated lung dysfunction, and inflammation leading to resolution of IRI. Additionally, in a preclinical murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. 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 significantly contribute to the resolution of post-LTx IRI.