The Cholinergic Anti-Inflammatory Response in the HIV Context
Delgado Vélez, Manuel
Lasalde-Dominicci, José A. (Consejero)
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Recent studies demonstrate that the central nervous system (CNS) and immune system interact with each other through a vagus nerve-dependent mechanism that involves afferent stimulation from peripheral inflammatory cytokines and the efferent release of the neurotransmitter acetylcholine (ACh). This circuit is called ‘the cholinergic anti-inflammatory pathway’ (CAP) because ACh binds to the alpha7 nicotinic acetylcholine receptor (α7-nAChR) in macrophages and inhibits the production of pro-inflammatory cytokines without altering the release of anti-inflammatory cytokines (1). The main objective of this thesis is to study the cholinergic anti-inflammatory response in the human immunodeficiency virus (HIV) scenario to better understand how the HIV affects the CAP and whether this understanding can help to comprehend and treat the chronic inflammation that affects HIV+ individuals. In humans, during the early phase of HIV infection (acute), a dysregulation of cytokines and chemokines occurs causing an increase that correlates with plasma viremia (2). During this phase, pro-inflammatory waves occur prior to anti-inflammatory factors detection in HIV infected donors, negatively affecting homeostasis. In fact, the long term consequences of this sustained dysregulation of pro- and anti-inflammatory mediators lead to chronic inflammation that lasts until death. Moreover, the inflammatory processes in these patients point toward HIV infection (3–8) and viral proteins, including gp120, (9) as causatives. For successful HIV infection, gp120 needs to bind CD4 and recruit CXCR4 or CCR5. Interestingly, gp120 has proven to bind to nAChRs-expressing cells from muscle and neuronal lineage (10) which could explain the infection of muscle and neuronal cells that are CD4 deficient (11,12). The lack of knowledge about the inflammatory role of the α7-nAChR in immune cells either recovered from HIV+ individuals or in vitro cells exposed to viral proteins lead us to examine the cholinergic anti-inflammatory response in the HIV context. Chapter 1 provides a general review on central and peripheral nAChRs. In addition, the available knowledge about CAP and the cholinergic anti-inflammatory reflex will be explained. Lastly, a review of inflammatory processes in HIV+ will be offered. Chapter 2, studies the in vitro effects of gp120 over α7-nAChR expression and discusses α7-nAChR studies in HIV-1 infected individuals. Moreover, it discusses inflammation assays to define the inflammatory phenotype of macrophages exposed to gp120. Chapter 3, examines the electrophysiological properties of α7-nAChR in human macrophages. Chapter 4, presents the α7-nAChR upregulation consequences regarding calcium mobilization and apoptosis. Chapter 5, addresses general conclusions. Finally, Chapter 6 presents and discusses a number of future perspectives for the current thesis.