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Divergent Roles for Neutrophils: Promoting and Resolving Inflammation?

Kulkarni, Upasana, PhD; Goldstein, Daniel, R., MD

doi: 10.1097/TP.0000000000002062
In View: Game Changer

1 Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI.

Received 28 November 2017. Revision received 4 December 2017.

Accepted 5 December 2017.

D.R.G. is supported by NIH grants HL127687, AG028082, AG050096, HL130669.

The author declares no conflicts of interest.

The study by Wang and colleagues will prompt transplant biologists to re-examine the roles of neutrophils.

Correspondence: Daniel R. Goldstein, 2800 Plymouth Road NCRC Building 20, 2nd Floor Ann Arbor, MI 48109. (

Ischemia reperfusion injury is currently an event that all solid organ transplants must endure. Neutrophils are one of the key cells types that are critical for the damage that occurs with ischemia reperfusion injury after organ implantation.1 Neutrophils may mediate their deleterious effects via the production of reactive oxygen species through enzymes, such as elastase and metalloproteinase, and neutrophil extracellular traps. There is emerging evidence that neutrophils may also promote immune suppression within tissues by becoming apoptotic and secreting anti-inflammatory molecules.2 Neutrophils that upregulate the chemokine receptor CXCR4 may also enhance the resolution of inflammation by promoting angiogenesis.3 However, the prevailing paradigm has been that neutrophils are proinflammatory after organ implantation (Figure 1). Thus, methods depleting neutrophils or mitigating their effector functions are expected to be beneficial for solid organ transplantation.



In contrast to the above paradigm, Wang and colleagues, from the laboratory of Dr. Paul Kubes, reported that neutrophils are critical to resolve sterile inflammation in an experimental thermal liver injury model in mice.4 The study used 2-photon microscopy and found that depleting neutrophils with a monoclonal antibody impaired the ability of the liver to heal after thermal injury.4 The study revealed that neutrophils neither underwent apoptosis, necrosis, nor phagocytosis by infiltrating monocytes within the inflamed liver.4 Instead, neutrophils reverse migrated from the site of injury to the circulation then arrested within the lungs, without inducing local tissue injury, before ultimately homing to the bone marrow.4 The ability of neutrophils to home to the bone marrow correlated with an upregulation of the chemokine receptor CXCR4 on neutrophils. The reverse migration of neutrophils to the circulation was also linked to an enhanced vessel growth in the injured liver and reduced liver injury, suggesting that the reverse migrating neutrophils promoted angiogenesis to enhance inflammation resolution.

The intriguing findings prompt one to reconsider the roles neutrophils in tissue injury. Do neutrophils provide a key angiogenic signal promoting vessel growth and healing in the thermal injury model used by Wang and colleagues? Or does the exiting of neutrophils from the liver allow for another angiogenic signal to emerge promoting blood vessel growth, ultimately supporting the resolution of tissue injury? Why do neutrophils home and arrest in the lung? One potential explanation is that the extensive pulmonary vasculature allows passing neutrophils to receive a signal that prompts their reprogramming.5 This reprogramming may then prevent neutrophils from inducing injury within the lung. Once reprogrammed, neutrophils traffic to the bone barrow for removal (Figure 1).

Clearly, the pathway of neutrophil reprogramming will need to be elucidated in more detail before applying the results of Wang and collegues to solid organ transplantation. Importantly, the thermal injury model used in the study is not one of ischemia reperfusion injury. Thus, key findings should therefore be reexamined in experimental models of ischemia reperfusion injury, such as a coronary ligation model of myocardial injury and ultimately applied in experimental organ transplant models including a heterotopic heart transplant model that will allowed visualization of neutrophils at the site of injury via 2 photon microscopies.6

Once both proinflammatory and anti-inflammatory roles of neutrophils have been established in experimental models of organ transplantation, subpopulations of neutrophils that contribute to either inflammation or resolving injury will need to be identified. As stated above, CXCR4 expression may identify neutrophils that promote angiogenesis. If divergent, functional subpopulations of neutrophils are identified, then their ontogeny will need to be determined, potentially by fate mapping studies, allowing to determine if one subpopulation of neutrophil is derived from the other. Hopefully, the study by Wang and colleagues will prompt transplant biologists to re-examine the roles of neutrophils in their models to determine if neutrophils are a heterogeneous population exhibiting divergent roles after organ transplantation. If so, therapies may be developed to deplete inflammatory neutrophils while augmenting those that will resolve injury. Transplant models will then allow one to define the impact of these distinct neutrophil populations on alloimmune responses.

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