Expression of interleukin-16 by microglial cells in inflammatory, autoimmune, and degenerative lesions of the rat brain

Abstract

Here we report a comparative analysis of interleukin-16 (IL-16) expression by microglial cells of the normal rat brain in trimethyltin (TMT) neurotoxicity, experimental autoimmune uveitis (EAU), encephalomyelitis (EAE), and viral infection (Borna disease, Borna disease virus) by immunohistochemistry. Striking differences were observed. In contrast to the human brain, IL-16 was not expressed constitutively in the rat brain. Remote activation of microglial cells of the optic tract in EAU did not result into IL-16 expression. TMT intoxication induced expression in microglial cells of the hippocampus. In EAE and BDV, massive IL-16⁺ microglial cells could be seen. Thus, IL-16 is a descriptor of microglial cell activation that discriminates between different disease models, and might be a valuable marker for the detection of microglia activation in human and rat central nervous system (CNS) diseases.

Introduction

Microglia constitute the first line of cellular defense mechanisms against central nervous system (CNS) diseases (for a review, see Hanisch, 2002), participating in the regulation of nonspecific inflammation as well as adaptive immune responses (Aloisi, 2001). Microglial cells respond to pathological stimuli like brain injury, inflammation, neurodegeneration, infection, or brain tumors with alterations in activation status and morphology (Benveniste, 1997). Microglial activation is generally characterized as a gradual transition from a quiescent stellate form to a macrophage-like morphology, which is accompanied by upregulation of surface antigens and formation of clusters. A variety of regulatory factors secreted by microglial cells are known and it needs to be established whether such activation-associated peptides can be used to compare microglia cell activation in different pathological settings. To this aim, we have used interleukin-16 (IL-16) immunohistochemistry to detect the activation of microglial cells in several experimental models.

IL-16, also known as lymphocyte chemoattractant factor (LCF) (Center and Cruikshank, 1982), is a proinflammatory cytokine that is produced by a variety of cells including microglia (for a review, see Kazatchkine, 1997). Recent in vivo studies have characterized IL-16 as an immunomodulatory cytokine that contributes to the regulatory process of CD4⁺ cell recruitment and activation at sites of inflammation in association with asthma and several autoimmune diseases (Cruikshank et al., 1998). It has been reported that the activity of IL-16 could be independent of CD4 (Mathy et al., 2000); therefore, there might exist another receptor for IL-16 apart from CD4, although it has been shown that IL-16 requires the expression of CD4 on target cells to induce a migratory signal (Cruikshank et al., 1994). Under pathological conditions, IL-16 expression might contribute to the inflammatory response by triggering the increase of intracellular Ca²⁺ levels, generation of inositol triphosphate, translocation of protein kinase C (PKC), and stimulation of the release of further proinflammatory cytokines such as IL-1β, IL-6, and TNF-α (Mathy et al., 2000). Expression of IL-16 can be downregulated by dexamethasone Arima et al., 1999, Center et al., 1996, Center and Cruikshank, 1982. In the human brain, IL-16 is constitutively expressed by a subpopulation of microglial cells, and it has been assumed that IL-16 may contribute to attract CD4⁺ lymphocytes across the blood–brain barrier (BBB) under pathological conditions (Schluesener et al., 1996). There are several reports on the expression of IL-16 in pathological human brains Mittelbronn et al., 2001, Schwab et al., 2001a, Schwab et al., 2001b, but corroborating animal data are lacking. Therefore, we have now performed a comparative analysis of IL-16 expression by rat microglial cells in the normal rat brain and four different pathologies: remote activation in the optical tract in experimental autoimmune uveitis (EAU), activation by neurotoxins in the trimethyltin (TMT) model, activation by autoimmune inflammation in encephalomyelitis (EAE), and activation by viral infection in Borna disease.