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MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant ischemia-reperfusion injury.
Leroy, Victoria; Manual Kollareth, Denny Joseph; Tu, Zhenxiao; Valisno, Jeff Arni C; Woolet-Stockton, Makena; Saha, Biplab K; Emtiazjoo, Amir M; Rackauskas, Mindaugas; Moldawer, Lyle L; Efron, Philip A; Cai, Guoshuai; Atkinson, Carl; Upchurch, Gilbert R; Sharma, Ashish K.
Afiliación
  • Leroy V; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Manual Kollareth DJ; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Tu Z; Department of Medicine, University of Florida, Gainesville, United States of America.
  • Valisno JAC; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Woolet-Stockton M; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Saha BK; Department of Medicine, University of Florida, Gainesville, United States of America.
  • Emtiazjoo AM; Department of Medicine, University of Florida, Gainesville, United States of America.
  • Rackauskas M; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Moldawer LL; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Efron PA; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Cai G; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Atkinson C; Department of Medicine, University of Florida, Gainesville, United States of America.
  • Upchurch GR; Department of Surgery, University of Florida, Gainesville, United States of America.
  • Sharma AK; Department of Surgery, University of Florida, Gainesville, United States of America.
JCI Insight ; 2024 Aug 22.
Article en En | MEDLINE | ID: mdl-39172530
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 MerTK (receptor Mer tyrosine kinase) 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 post-LTx patients 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-CR (cleavage resistant) mice. A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients was observed compared to healthy subjects. In the murine IRI model, significant increase in M-MDSCs, MerTK expression, 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos