Laboratory of Neuroregeneration, Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Brain mononuclear phagocytes (MP, bone marrow monocyte-derived macrophages, perivascular macrophages, and microglia) function to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. MP are activated by a variety of environmental cues and such inflammatory responses elicit cell injury and death in the nervous system. MP immunoregulatory responses include secretion of neurotoxic factors, mobilization of adaptive immunity, and cell chemotaxis. This incites tissue remodelling and blood-brain barrier dysfunction. As disease progresses, MP secretions engage neighboring cells in a vicious cycle of autocrine and paracrine amplification of inflammation leading to tissue injury and ultimately destruction. Such pathogenic processes tilt the balance between the relative production of neurotrophic and neurotoxic factors and to disease progression. The ultimate effects that brain MP play in disease revolves "principally" around their roles in neurodegeneration. Importantly, common functions of brain MP in neuroimmunity link highly divergent diseases (for example, human immunodeficiency virus type-one associated dementia, Alzheimer's disease and Parkinson's disease). Research into this process from our own laboratories and those of others seek to harness MP inflammatory processes with the intent of developing therapeutic interventions that block neurodegenerative processes and improve the quality of life in affected people.
"After entering the CNS, infected monocytes, lymphocytes, and macrophages release various mediators including cytokines, reactive oxygen, and other molecules that have the potential to induce neurotoxicity (Ciborowski and Gendelman 2006; Ricardo-Dukelow et al. 2007). In addition to disrupting normal function of CNS cells these mediators also stimulate uninfected CNS monocytes, macrophages and lymphocytes to release potential neurotoxins (Kadiu et al. 2005; Persidsky and Gendelman 2003). Galectin-1 is an immunomodulater. "
[Show abstract][Hide abstract] ABSTRACT: Galectin-1, an adhesion molecule, is expressed in macrophages and implicated in human immunodeficiency virus (HIV-1) viral adsorption. In this study, we investigated the effects of methamphetamine on galectin-1 production in human monocyte derived macrophages (MDM) and the role of galectin-1 in methamphetamine potentiation of HIV-1 infection. Herein we show that levels of galectin-1 gene and protein expression are significantly increased by methamphetamine. Furthermore, concomitant incubation of MDM with galectin-1 and methamphetamine facilitates HIV-1 infection compared to galectin-1 alone or methamphetamine alone. We utilized a nanotechnology approach that uses gold nanorod (GNR)-galectin-1 siRNA complexes (nanoplexes) to inhibit gene expression for galectin-1. Nanoplexes significantly silenced gene expression for galectin-1 and reversed the effects of methamphetamine on galectin-1 gene expression. Moreover, the effects of methamphetamine on HIV-1 infection were attenuated in the presence of the nanoplex in MDM.
"Within the CNS, the main executors of innate immunity are perivascular macrophages and parenchymal microglia . Resting microglia are highly ramified with branched processes and have critical physiologic roles, including determination of neuronal fate, migration, axonal growth and synaptic remodeling [58,59]. "
[Show abstract][Hide abstract] ABSTRACT: Chronic neuroinflammation is an important component of Alzheimer's disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer's because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer's disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression.
To investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer's disease mice (harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes) with the small molecule tumor necrosis factor-α inhibitors, 3,6'-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-α. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints.
3,6'-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice. In comparison to non-transgenic controls, triple transgenic Alzheimer's disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-α, which was reduced after treatment with 3,6'-dithiothalidomide.
These results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer's disease.
Journal of Neuroinflammation 05/2012; 9(1):99. DOI:10.1186/1742-2094-9-99 · 5.41 Impact Factor
"The CD14lowCD16+ monocytes express higher levels of proinflammatory cytokines than CD14+CD16- monocytes, with a higher capacity for antigen presentation, and are increased in inflammatory and infectious diseases in humans . Macrophage/microglial inflammatory activities have been shown to influence a number of neurodegenerative diseases including human immunodeficiency virus (HIV)-associated dementia, Alzheimer's disease, Parkinson's disease, stroke, brain and spinal cord trauma . In HAM/TSP, the expression of proinflammatory cytokines such as IL-1β, TNF-α and IFN-γ is detected in peripheral blood mononuclear cells (PBMCs) as well as in perivascular infiltrating macrophages and microglia in the spinal cords of patients with HAM/TSP [26,27]. "
[Show abstract][Hide abstract] ABSTRACT: The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases.
Phenotypic analysis of CD14⁺ monocytes in HAM/TSP patients demonstrated high expression of CX3CR1 and HLA-DR in CD14lowCD16⁺ monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-α and IL-1β in cultured CD14⁺ cells of HAM/TSP patients. CD14⁺ cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4⁺ T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-α expression in CD14⁺ cells and IL-1β release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-γ expression in CD8⁺ T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-γ expression in CD8⁺ T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14⁺ cells.
These results demonstrate that minocycline directly inhibits the activated MPs and that the downregulation of MP function can modulate CD8⁺ T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.