CD4(+) T cell-derived NGAL modifies the outcome of Ischemic acute kidney Injury
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Abstract CD4+ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI). However, the underlying mechanisms of CD4+ T cell–mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4+ T cells after ischemia compared with normal mouse kidney. Unexpectedly, the lipocalin-2 (Lcn2) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the highest fold increase (∼60). The NGAL increase in CD4+ T cells during AKI was confirmed at the mRNA level with quantitative real-time PCR and at the protein level with ELISA. NGAL is a potential biomarker for the early detection of AKI and has multiple potential biological functions. However, the role of NGAL produced by CD4+ T cells is not known. We found that ischemic AKI in NGAL knockout (KO) mice had worse renal outcomes compared with wild-type (WT) mice. Adoptive transfer of NGAL-deficient CD4+ T cells from NGAL KO mice into CD4 KO or WT mice led to worse renal function than transfer of WT CD4+ T cells. In vitro–simulated ischemia/reperfusion showed that NGAL-deficient CD4+ T cells express higher levels of IFN-γ mRNA compared with WT CD4+ T cells. In vitro differentiation of naive CD4+ T cells to Th17, Th1, and Th2 cells led to significant increase in Lcn2 expression. Human kidney CD4+ T cell NGAL also increased significantly after ischemia. These results demonstrate an important role for CD4+ T cell NGAL as a mechanism by which CD4+ T cells mediate AKI and extend the importance of NGAL in AKI beyond diagnostics.
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Many effectors of microbial iron withdrawal have direct or indirect impact on acquired immunity, such as the function of lymphocyte subsets.
“Furthermore, many effectors of microbial iron withdrawal have direct or indirect impact on acquired immunity such as the function of lymphocyte subsets (Dai et al., 2009;Hedges et al., 2013;Lee et al., 2020;Stober et al., 2007).”
From Iron in infection and immunity (2020) · cites this paper as Lee et al., 2020
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Iron in infection and immunity
Nairz, M., & Weiss, G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100864 · Cited by 359 · see citing works
- Authors
- Lee, S. A., Noel, S., Kurzhagen, J. T., Sadasivam, M., Pierorazio, P. M., Arend, L. J., Hamad, A. R., & Rabb, H.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Noel, Sanjeev
- Rabb, Hamid
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-02-01
- Volume
- 204
- Issue
- 3
- Pages
- 586-595
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC6981061
- OpenAlex
- W2997996943
- Cited by
- 41
- References
- 55
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 3 · 2018: 1
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01dk104662-06)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK123342, R01-DK104662, R01DK111209)
- Topics
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Keywords
- neutrophil gelatinase-associated lipocalin, CD4+ T cells, ischemic acute kidney injury, ischemia-reperfusion injury, adoptive T cell therapy, interferon-gamma, Th17 cells, Th1 cells, Th2 cells, T cell differentiation, renal function
- MeSH terms
- Lipocalin-2, Animals, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Humans, Interferon-gamma, Ischemia, Kidney, Male, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes, Up-Regulation, Sequence Analysis, RNA, Mice, Knockout, Mice, Acute Kidney Injury
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