Ischemia reperfusion injury facilitates lung allograft acceptance through IL-33-mediated activation of donor-derived IL-5 producing group 2 innate lymphoid cells

Guo, Yanxia; Mei, Zhongcheng; Li, Dongge; Banerjee, Anirban; Khalil, May; Burke, Allen; Ritter, Jon H.; Lau, Christine L.; Kreisel, Daniel; Gelman, Andrew E.; Jacobsen, Elizabeth A.; Luzina, Irina G.; Atamas, Sergei P.; Krupnick, Alexander S.

doi:10.1111/ajt.17084

Cited by 9 publications

(6 citation statements)

References 67 publications

(135 reference statements)

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“…In lung transplantation, donor tissue NK cells and ILC1s are altered in patients with severe PGD ( 40 ). Conversely, ILC2s and ILC3s may contribute to lung transplant tolerance through a variety of mechanisms ( 41 , 42 ). Here, we found that CD49a + NK cells, likely tissue-resident in origin, trafficked into the airways as they constituted a significant proportion of the sampled BAL NK cells.…”

Section: Discussionmentioning

confidence: 99%

CCR5 drives NK cell–associated airway damage in pulmonary ischemia-reperfusion injury

Santos,

Wang,

Shemesh

et al. 2023

JCI Insight

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Primary graft dysfunction (PGD) limits clinical benefit after lung transplantation, a life-prolonging therapy for patients with end-stage disease. PGD is the clinical syndrome resulting from pulmonary ischemia-reperfusion injury (IRI), driven by innate immune inflammation. We recently demonstrated a key role for NK cells in the airways of mouse models and human tissue samples of IRI. Here, we used 2 mouse models paired with human lung transplant samples to investigate the mechanisms whereby NK cells migrate to the airways to mediate lung injury. We demonstrate that chemokine receptor ligand transcripts and proteins are increased in mouse and human disease. CCR5 ligand transcripts were correlated with NK cell gene signatures independently of NK cell CCR5 ligand secretion. NK cells expressing CCR5 were increased in the lung and airways during IRI and had increased markers of tissue residency and maturation. Allosteric CCR5 drug blockade reduced the migration of NK cells to the site of injury. CCR5 blockade also blunted quantitative measures of experimental IRI. Additionally, in human lung transplant bronchoalveolar lavage samples, we found that CCR5 ligand was associated with increased patient morbidity and that the CCR5 receptor was increased in expression on human NK cells following PGD. These data support a potential mechanism for NK cell migration during lung injury and identify a plausible preventative treatment for PGD.

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Section: Discussionmentioning

confidence: 99%

CCR5 drives NK cell–associated airway damage in pulmonary ischemia-reperfusion injury

Santos,

Wang,

Shemesh

et al. 2023

JCI Insight

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“…39 These type 2 immune cells support a large group of alternatively activated macrophages that support tissue regeneration and repair, thus protecting against a loss of function during infection. 109 However, a recent study by Guo et al found that the IRI upregulated IL-33, which promoted IL-5 production by graft-resident ILC2s to increase local eosinophils supporting tolerance after lung transplant. 109 Interestingly, this IL-33/IL-5/eosinophil-mediated mechanism relied on immunosuppression to preserve donor ILC2s.…”

Section: Il-33 In Transplantationmentioning

confidence: 97%

“…109 However, a recent study by Guo et al found that the IRI upregulated IL-33, which promoted IL-5 production by graft-resident ILC2s to increase local eosinophils supporting tolerance after lung transplant. 109 Interestingly, this IL-33/IL-5/eosinophil-mediated mechanism relied on immunosuppression to preserve donor ILC2s. These exciting data support the concept that IRI not only triggers pro-inflammatory pathways but also initiates reparative and regenerative mechanisms.…”

Section: Il-33 In Transplantationmentioning

confidence: 97%

The Reparative Roles of IL-33

Saba

Turnquist

2023

Transplantation

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When discovered in the early 2000s, interleukin-33 (IL-33) was characterized as a potent driver of type 2 immunity and implicated in parasite clearance, as well as asthma, allergy, and lung fibrosis. Yet research in other models has since revealed that IL-33 is a highly pleiotropic molecule with diverse functions. These activities are supported by elusive release mechanisms and diverse expression of the IL-33 receptor, STimulation 2 (ST2), on both immune and stromal cells. Interestingly, IL-33 also supports type 1 immune responses during viral and tumor immunity and after allogeneic hematopoietic stem cell transplantation. Yet the IL-33–ST2 axis is also critical to the establishment of systemic homeostasis and tissue repair and regeneration. Despite these recent findings, the mechanisms by which IL-33 governs the balance between immunity and homeostasis or can support both effective repair and pathogenic fibrosis are poorly understood. As such, ongoing research is trying to understand the potential reparative and regulatory versus pro-inflammatory and pro-fibrotic roles for IL-33 in transplantation. This review provides an overview of the emerging regenerative role of IL-33 in organ homeostasis and tissue repair as it relates to transplantation immunology. It also outlines the known impacts of IL-33 in commonly transplanted solid organs and covers the envisioned roles for IL-33 in ischemia-reperfusion injury, rejection, and tolerance. Finally, we give a comprehensive summary of its effects on different cell populations involved in these processes, including ST2+ regulatory T cells, innate lymphoid cell type 2, as well as significant myeloid cell populations.

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“…Furthermore, IL-33 is also known to activate MDSCs to delay heart allograft rejection in mice, which was not investigated by the authors ( 185 , 257 ). Donor-derived ILC2s activated by IRI were recently shown to enhance eosinophil recruitment to the allograft following lung transplantation, leading to reduced T cell infiltration and attenuating rejection at seven days post-transplant ( 261 ). Of note, this axis was dependent on donor ILC2s, rather than infiltrating recipient ILC2s, suggesting additional work will be required to differentiate the roles of donor and recipient ILC2s in other transplant models ( 261 ).…”

Section: Engineering Tolerance and The Development Of Innate Immune C...mentioning

confidence: 99%

Innate immune cellular therapeutics in transplantation

Ott

Cuenca

2023

Front. Transplant.

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Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed “trained immunity.” Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation.

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Ischemia reperfusion injury facilitates lung allograft acceptance through IL-33-mediated activation of donor-derived IL-5 producing group 2 innate lymphoid cells

Cited by 9 publications

References 67 publications

CCR5 drives NK cell–associated airway damage in pulmonary ischemia-reperfusion injury

CCR5 drives NK cell–associated airway damage in pulmonary ischemia-reperfusion injury

The Reparative Roles of IL-33

Innate immune cellular therapeutics in transplantation

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