Voltage-gated Potassium Channel Modulation of Neurotoxic Activity in Human Immunodeficiency Virus Type-1(HIV-1)-Infected Macrophages

Abstract

Macrophages play an important role in brain immune and inflammatory responses. They are also critical cells in mediating the pathology of neurodegenerative disorders such as HIV-associated dementia. This is largely through their capacity to secrete a variety of bioactive molecules such as cytokines, leading to neuronal dysfunction and/or death. Accumulating evidence indicates that voltage-gated potassium (Kv) channels play a pivotal role in the modulation of macrophage proliferation, activation, and secretion. Blockade of Kv channels by specific antagonists decreases macrophage cytokine production and ameliorates macrophage-associated neuronal injury. These results suggest that Kv channels might become a potential target for the development of new therapeutic strategies for chronic inflammatory diseases.

Monocyte Chemotactic Protein-1 Regulates Voltage-Gated K+ Channels and Macrophage Transmigration

“…In the present study, we have demonstrated that MCP-1, a glial-derived cytokine, enhanced outward K + currents and macrophage transmigration via regulation of Kv channel expression and channel activity. Our results herein fully support works by others demonstrating the expression of Kv channels in monocytes and macrophages (Mackenzie et al, 2003; Vicente et al, 2005; Vicente et al, 2006; Irvine et al, 2007; Villalonga et al, 2007). Voltage-gated K + channels including Kv1.3 channels are operative in blood-borne macrophages, tissue macrophages, and microglia, and are prominently induced concomitant with M-CSF-dependent proliferation.…”

“…It is well known that differential channel regulation affects intracellular signals and is linked to macrophage activation and differentiation as well as to immune, morphological, and migratory responses of the cells (DeCoursey et al, 1996; Mackenzie et al, 2003; Fordyce et al, 2005; Rus et al, 2005; Vicente et al, 2005; Irvine et al, 2007). LPS-activation, for example, differentially regulates channel expression, as demonstrated by the induction of Kv1.3 channels and down-regulation of Kir2.1 channels.…”

“…For T cells, these channels are important since they serve as a primary regulator and affector of cell activation, as well as in maintaining resting membrane potential and ion homeostasis (Estes et al, 2008; Poulopoulou et al, 2008). Importantly, less is known about the functional roles of channels in disease; although, Kv1.3 blockade has been shown to reduce proinflammatory cytokine secretion and cell proliferation (Irvine et al, 2007), as well as slow cell movement. Such findings serve as a foundation for investigations into whether channel modulation can be utilized as a therapeutic target for autoimmune disease such as multiple sclerosis as suggested from studies showing that selective Kv1.3 channel blockers diminish disease progression in experimental allergic encephalomyelitis (Gonsette, 2004; Vianna-Jorge and Suarez-Kurtz, 2004; Beeton and Chandy, 2005; Panyi, 2005; Rus et al, 2005; Beraud et al, 2006).…”

Voltage-dependent K+-channel responses during activation and damage in alveolar macrophages induced by quartz particles

“…Recently some experiments [14][15][16][17][18] found that activation of macrophages involved the change of membrane K + current which was closely associated with such cell functions as secretion of cytokines. The voltage-dependent K + channel in macrophages was intensively studied [19][20][21][22][23] . Silica particles, however, were not covered by those studies.…”

Neuroimmune Pharmacology Expanding in Asia Pacific Rim

“…Sheng-Di Chen's group reviewed the importance of CD200-CD200R interaction for microglia activation and its role in the pathogenesis of PD (Wang 2007). Huangui Xiong's laboratory summarized recent advances made in voltage-gated potassium channel for the regulation of macrophage-mediated neurotoxicity in HAD (Irvine et al 2007). Although the etiology of both diseases are different, it is now commonly accepted that microglia activation plays a pivotal role in the pathogenesis of many neurodegenerative disorders, including HAD, AD, and PD.…”