OSTEOPONTIN: A KEY LINK BETWEEN IMMUNITY, INFLAMMATION AND THE CENTRAL NERVOUS SYSTEM

Abstract

Osteopontin (OPN) is a pro-inflammatory cytokine that can be secreted from many cells including activated macrophages and T-lymphocytes. Elevated levels of osteopontin in the plasma, cerebrospinal fluid or brain of individuals with neurodegenerative diseases such as multiple sclerosis (MS), Parkinson's and Alzheimer's disease and more recently in HIV-associated neurocognitive disorder has been reported. However, except for the case of MS, little is known regarding the molecular mechanisms by which OPN may exacerbate disease. Alternatively, OPN through its ability to promote cell survival may in some contexts function in the brain in a protective capacity. OPN has several protein motifs that allow it to engage with several different signaling pathways involved in immunity and inflammation. A better understanding of the cellular pathways that are regulated by OPN in cells of the central nervous system is required to uncover its putative role in neuronal homeostasis.

Keywords: CD44; HIV-associated neurocognitive disorder; Integrin; Macrophage; Microglia; Neurodegeneration.

Figure 1

Osteopontin (OPN) as an inflammatory mediator at the neuroimmune axis. OPN secreted from activated macrophages and microglia, and possibly other cells in the CNS can, through the release of specific cytokines such as IL-12, stimulate cell-mediated immune responses of the adaptive arm of the immune system. Inadvertently, OPN via activation of signaling pathways that induce NF-κB, can upregulate HIV-1 replication, thus exacerbating virus replication. OPN can also modulate the expression of other inflammatory cytokines. When OPN release is chronic and sustained, toxicity can result that can lead to the dysfunction and degeneration of neurons and perhaps of glia as well. Alternatively, in models of hypoxic ischemia, OPN can promote cell survival by inhibition of apoptotic pathways.