Indiana University-Purdue University Indianapolis (IUPUI) / Acute kidney injury (AKI) affects millions of patients worldwide yet has few
treatment options. There is a critical need to identify novel interventions for AKI, especially
approaches targeting cell types that are central to the disease, such as neutrophils.
Neutrophils are professional phagocytic cells that respond early to tissue injury. In rodent
models of severe ischemic-reperfusion-injury AKI, neutrophils transiently infiltrate the
injured kidney, appearing within 6 hours, and are gone by 72 hours. These infiltrating
neutrophils are considered proinflammatory and harmful to tissue repair and recovery of
kidney function. However, neutrophils can exhibit atypical activity such as antigen
presentation and have a central role in recovery from myocardial ischemic injury.
Furthermore, little is known of neutrophil polarization, atypical activity, or neutrophil
diversity in AKI. Lastly, the kidney generated and renal-protective immunomodulatory
protein uromodulin (Tamm-Horsfall Protein, THP) regulates granulopoiesis. In the
absence of uromodulin, there is a systemic increase in neutrophils and mouse kidneys are
sensitive to injury in AKI. To elucidate neutrophil diversity in AKI and their sensitivity to
uromodulin, I performed a series of single-cell sequencing experiments to generate
transcriptional profiles of neutrophils from the blood and kidneys of wild-type and THPknockout
mice after renal ischemic-reperfusion-injury (IRI). Neutrophil diversity was
detected following IRI of the mouse kidney in the blood and kidney. The distribution of
subpopulations was sensitive to the kidney milieu. Within the kidney, this diversity and
the transcriptional programs of neutrophil subpopulations was sensitive to the severity of
ischemic injury. Lastly, Cxcl3 was uniquely upregulated in specific neutrophils after severe
ischemic injury. Using single-cell sequencing of uromodulin knock-out mice, I detected
the upregulation of toll-like receptor pathways and complement cascades across
neutrophil subpopulations in a THP sensitive manner. Furthermore, CXCR2 ligand
expression was a combination of moderate and severe injury in wild-type mice. This
confirmed previously reported cytokine dysregulation in the uromodulin knock-out mouse
after IRI and uncovers a novel role for Cxcl3. Thus, upon revisiting the well-studied
neutrophil, I have uncovered novel neutrophil diversity that correlates with recovery of
kidney function in AKI and suggests new roles for an old player.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/24095 |
| Date | 09 1900 |
| Creators | Winfree, Seth |
| Contributors | El-Achkar, Tarek M., Dagher, Pierre C., Day, Richard N., Williams, James C., Jr. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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