Abstract |
Neutrophil extracellular traps (NETs) have been shown to worsen acute pulmonary injury including after lung transplantation. The breakdown of NETs by DNAse-1 can help restore lung function, but whether there is an impact on allograft tolerance remains less clear. Using intravital 2-photon microscopy, we analyzed the effects of DNAse-1 on NETs in mouse orthotopic lung allografts damaged by ischemia-reperfusion injury. Although DNAse-1 treatment rapidly degrades intragraft NETs, the consequential release of NET fragments induces prolonged interactions between infiltrating CD4+ T cells and donor-derived antigen presenting cells. DNAse-1 generated NET fragments also promote human alveolar macrophage inflammatory cytokine production and prime dendritic cells for alloantigen-specific CD4+ T cell proliferation through activating toll-like receptor (TLR) - Myeloid Differentiation Primary Response 88 (MyD88) signaling pathways. Furthermore, and in contrast to allograft recipients with a deficiency in NET generation due to a neutrophil-specific ablation of Protein Arginine Deiminase 4 (PAD4), DNAse-1 administration to wild-type recipients promotes the recognition of allo- and self-antigens and prevents immunosuppression-mediated lung allograft acceptance through a MyD88-dependent pathway. Taken together, these data show that the rapid catalytic release of NET fragments promotes innate immune responses that prevent lung transplant tolerance.
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Authors | Davide Scozzi, Xingan Wang, Fuyi Liao, Zhiyi Liu, Jihong Zhu, Katy Pugh, Mohsen Ibrahim, Hsi-Min Hsiao, Mark J Miller, Guo Yizhan, Thalachallour Mohanakumar, Alexander S Krupnick, Daniel Kreisel, Andrew E Gelman |
Journal | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
(Am J Transplant)
Vol. 19
Issue 4
Pg. 1011-1023
(04 2019)
ISSN: 1600-6143 [Electronic] United States |
PMID | 30378766
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons. |
Chemical References |
- Inflammation Mediators
- Deoxyribonucleases
|
Topics |
- Animals
- Cells, Cultured
- Dendritic Cells
(immunology)
- Deoxyribonucleases
(metabolism)
- Enzyme-Linked Immunosorbent Assay
- Extracellular Traps
(immunology, metabolism)
- Humans
- Immunity, Innate
(immunology)
- Inflammation Mediators
(metabolism)
- Lung Transplantation
- Macrophages, Alveolar
(cytology, immunology, metabolism)
- Mice
- Mice, Inbred BALB C
- Reperfusion Injury
- Transplantation Tolerance
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