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Suppression of HIV-associated Macrophage Activation by a p75 Neurotrophin Receptor Ligand

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Abstract

Previous studies indicated that nerve growth factor (NGF) and proNGF differentially regulate the phenotype of macrophages and microglia via actions at tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptors (p75NTR), respectively. The ability of HIV gp120 and virions to induce the secretion of factors toxic to neurons was suppressed by NGF and enhanced by proNGF, suggesting the potential for neurotrophin based “anti-inflammatory” interventions. To investigate the “anti-inflammatory” potential of the p75NTR ligand, LM11A-31, we treated cultured macrophages and microglia with HIV gp120 in the presence or absence of the ligand and evaluated the morphological phenotype, intrinsic calcium signaling, neurotoxic activity and proteins in the secretome. LM11A-31 at 10 nM was able to suppress the release of neurotoxic factors from both monocyte-derived macrophages (MDM) and microglia. The protective effects correlated with a shift in morphology and a unique secretory phenotype rich in growth factors that overrode the actions of HIV gp120. The protein pattern was generally consistent with anti-inflammatory, phagocytic and tissue remodeling functions. Although the toxic factor(s) and the source of the neuroprotection were not identified, the data indicated that an increased degradation of NGF induced by HIV gp120 was likely to contribute to neuronal vulnerability. Although substantial work is still needed to reveal the functions of many proteins in the mononuclear phagocyte secretome, such as growth and differentiation factors, the data clearly indicate that the ligand LM11A-31 has excellent therapeutic potential due to its ability to induce a more protective phenotype that restricts activation by HIV.

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Data Availability

A complete set of array data is provided in the Online Resources. Any additional data will be made available on request.

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Acknowledgements

These studies were funded by National Institutes of Health Grants: R01 NS083164 (RBM), R01 MH085606 (RBM), R21 AG056924 (RBM), F31 MH101019 (KSW) and F32 HL085025 (DAK).

Funding

R01 NS083164 (RBM), R01 MH085606 (RBM), R21 AG056924 (RBM), F31 MH101019 (KSW) and F32 HL085025 (DAK).

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Authors and Affiliations

  1. Department of Neurology, University of North Carolina, Chapel Hill, NC, 27599, USA

    Deirdre A. Killebrew, Kimberly S. Williams, Youmei Xie & Rick B. Meeker

  2. Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, 27599, USA

    Kimberly S. Williams & Rick B. Meeker

  3. DNA Sciences Inc, Stony Brook, NY, 11794, USA

    Deirdre A. Killebrew

  4. Department of Environmental and Health Sciences, Spelman College, Atlanta, GA, 30314, USA

    Kimberly S. Williams

  5. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Frank Longo

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  1. Deirdre A. Killebrew
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  2. Kimberly S. Williams
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  3. Youmei Xie
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  4. Frank Longo
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  5. Rick B. Meeker
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Contributions

Preparation of materials, study design, array analysis, data summaries and editing of the manuscript were done by Deirdre A. Killebrew and Kimberly S. Williams who contributed equally to the studies. Youmei Xie provided the western blot data. Frank Longo provided an unrestricted gift of LM11A-31, consulted on the use of the compound, and reviewed the manuscript. Rick B Meeker participated in the design of experiments, wrote the first draft of the manuscript, provided funding for the studies, reviewed the data and participated in the analysis of the data. All authors read and approved the final manuscript.

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Correspondence to Rick B. Meeker.

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Competing Interests

Dr. Longo, co-author, is listed as an inventor on patents relating to a compound in this report that is assigned to the University of North Carolina. Dr. Longo is a principal of, and has financial interest in PharmatrophiX, a company focused on the development of small molecule ligands for neurotrophin receptors that has licensed several of these patents. Dr. Longo provided the compound, LM11A-31, for these studies as an unrestricted gift. He consulted on the use of the compound and reviewed the manuscript but did not participate in the design or conduction of any experiments.

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Killebrew, D.A., Williams, K.S., Xie, Y. et al. Suppression of HIV-associated Macrophage Activation by a p75 Neurotrophin Receptor Ligand. J Neuroimmune Pharmacol 17, 242–260 (2022). https://doi.org/10.1007/s11481-021-10002-x

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