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Article

Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat

by
Giusi Ianiro
1,†,
Veronica D’Ezio
2,†,
Ludovica Carpinelli
2,
Cecilia Casella
2,
Maria Carmela Bonaccorsi di Patti
3,
Luigi Rosa
4,
Piera Valenti
4,
Marco Colasanti
2,
Giovanni Musci
1,
Antimo Cutone
1,*,‡ and
Tiziana Persichini
2,*,‡
1
Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy
2
Department of Science, University “ROMA TRE”, 00146 Rome, Italy
3
Department of Biochemical Sciences, Sapienza University of Roma, 00185 Rome, Italy
4
Department of Public Health and Infectious Diseases, Sapienza University of Roma, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(9), 7947; https://doi.org/10.3390/ijms24097947
Submission received: 4 April 2023 / Revised: 24 April 2023 / Accepted: 24 April 2023 / Published: 27 April 2023
(This article belongs to the Special Issue Lactoferrin, the Moonlighting Protein of Innate Immunity)
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Abstract

The Trans-Activator of Transcription (Tat) of Human Immunodeficiency Virus (HIV-1) is involved in virus replication and infection and can promote oxidative stress in human astroglial cells. In response, host cells activate transcription of antioxidant genes, including a subunit of System Xc− cystine/glutamate antiporter which, in turn, can trigger glutamate-mediated excitotoxicity. Here, we present data on the efficacy of bovine Lactoferrin (bLf), both in its native (Nat-bLf) and iron-saturated (Holo-bLf) forms, in counteracting oxidative stress in U373 human astroglial cells constitutively expressing the viral protein (U373-Tat). Our results show that, dependent on iron saturation, both Nat-bLf and Holo-bLf can boost host antioxidant response by up-regulating System Xc− and the cell iron exporter Ferroportin via the Nuclear factor erythroid 2-related factor (Nrf2) pathway, thus reducing Reactive Oxygen Species (ROS)-mediated lipid peroxidation and DNA damage in astrocytes. In U373-Tat cells, both forms of bLf restore the physiological internalization of Transferrin (Tf) Receptor 1, the molecular gate for Tf-bound iron uptake. The involvement of astrocytic antioxidant response in Tat-mediated neurotoxicity was evaluated in co-cultures of U373-Tat with human neuronal SH-SY5Y cells. The results show that the Holo-bLf exacerbates Tat-induced excitotoxicity on SH-SY5Y, which is directly dependent on System-Xc− upregulation, thus highlighting the mechanistic role of iron in the biological activities of the glycoprotein.
Keywords: HIV-1 Tat; Lactoferrin; iron saturation; oxidative stress; neurotoxicity; astrocytes; Nrf-2; System Xc− HIV-1 Tat; Lactoferrin; iron saturation; oxidative stress; neurotoxicity; astrocytes; Nrf-2; System Xc−

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MDPI and ACS Style

Ianiro, G.; D’Ezio, V.; Carpinelli, L.; Casella, C.; Bonaccorsi di Patti, M.C.; Rosa, L.; Valenti, P.; Colasanti, M.; Musci, G.; Cutone, A.; et al. Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat. Int. J. Mol. Sci. 2023, 24, 7947. https://doi.org/10.3390/ijms24097947

AMA Style

Ianiro G, D’Ezio V, Carpinelli L, Casella C, Bonaccorsi di Patti MC, Rosa L, Valenti P, Colasanti M, Musci G, Cutone A, et al. Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat. International Journal of Molecular Sciences. 2023; 24(9):7947. https://doi.org/10.3390/ijms24097947

Chicago/Turabian Style

Ianiro, Giusi, Veronica D’Ezio, Ludovica Carpinelli, Cecilia Casella, Maria Carmela Bonaccorsi di Patti, Luigi Rosa, Piera Valenti, Marco Colasanti, Giovanni Musci, Antimo Cutone, and et al. 2023. "Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat" International Journal of Molecular Sciences 24, no. 9: 7947. https://doi.org/10.3390/ijms24097947

APA Style

Ianiro, G., D’Ezio, V., Carpinelli, L., Casella, C., Bonaccorsi di Patti, M. C., Rosa, L., Valenti, P., Colasanti, M., Musci, G., Cutone, A., & Persichini, T. (2023). Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat. International Journal of Molecular Sciences, 24(9), 7947. https://doi.org/10.3390/ijms24097947

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