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. 2000 Apr;156(4):1441-53.
doi: 10.1016/S0002-9440(10)65013-4.

Chemokine and chemokine-receptor expression in human glial elements: induction by the HIV protein, Tat, and chemokine autoregulation

C M McManus  1 , K Weidenheim, S E Woodman, J Nunez, J Hesselgesser, A Nath, J W Berman
Affiliations

Chemokine and chemokine-receptor expression in human glial elements: induction by the HIV protein, Tat, and chemokine autoregulation

C M McManus et al. Am J Pathol. 2000 Apr.

Abstract

Human immunodeficiency virus (HIV) encephalitis is a prominent pathology seen in children infected with HIV. Immunohistochemical analyses of pediatric brain tissue showed distinct differences in expression of C-C chemokines and their receptors between children with HIV encephalitis and those with non-CNS-related pathologies. Evidence suggests that soluble factors such as HIV Tat released from HIV-infected cells may have pathogenic effects. Our results show Tat effects on chemokines and their receptors in microglia and astrocytes as well as chemokine autoregulation in these cells. These results provide evidence for the complex interplay of Tat, chemokines, and chemokine receptors in the inflammatory processes of HIV encephalitis and illustrate an important new role for chemokines as autocrine regulators.

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Figures

Figure 1.
Figure 1.
Immunohistochemical analysis of chemokine expression in HIV encephalitis. Immunohistochemistry of both HIV encephalitic pediatric brain tissue and normal control tissues. A and B: Staining with MIP-1α. The tissue in A is from an encephalitogenic HIV-infected individual. B: The lack of immunoreactivity of normal brain tissue for MIP-1α. C and D: Staining of MIP-1β in HIV encephalitis both in the parenchyma of the tissue (C) and surrounding a vessel (D). MCP-1 expression in HIV encephalitis is shown in E and F. This illustrates reactivity of the endothelium (E) and astrocytes and microglia in the parenchyma (F). G: A normal brain stained for MCP-1. H: a representative isotype matched control for these antibodies. Magnification: A–H, ×82.5.
Figure 2.
Figure 2.
Immunohistochemical analysis of chemokine receptor expression. Immunohistochemistry illustrating the expression of chemokine receptors in pediatric HIV encephalitis. CCR2 is expressed in HIV encephalitis (A) but is minimally detectable in normal brains (B). CCR5 immunoreactivity was seen on neurons, astrocytes, microglia, and mononuclear cells (C and D). This receptor is seen in both normal (D) and encephalitic brains (C). Similar to CCR5, CXCR4 is expressed in normal brain (F) and HIV encephalitis (E) but appears to be more intense in encephalitogenic tissues (E). Magnification: A–F, ×82.5.
Figure 3.
Figure 3.
Tat induces chemokine expression by human fetal microglia. Chemokine ELISA analyses shown in (A, B, and C) illustrate the protein expression of MIP-1α, MIP-1β, and MCP-1 after treatment with varying doses of Tat. A and B: Significant induction of MIP-1α and MIP-1β (P ≤ 0.05) after 100 ng/ml treatment with Tat. MCP-1 (C) is significantly induced (P ≤ 0.05) at all doses of Tat after 24 hours of treatment (n = 5). Each symbol denotes a separate donor and is used to illustrate the variability in data obtained from individual samples used in these experiments.
Figure 4.
Figure 4.
Tat induces chemokine expression by human fetal astrocytes. Analysis of protein expression for these chemokines by ELISA shows picogram amounts of MIP-1α and MIP-1β induced by 100 ng/ml of Tat (n = 5) (A). B: MCP-1 is significantly induced (P ≤ 0.05) after 100 ng/ml treatment of astrocytes for 24 hours (n = 5). Each symbol denotes a separate donor. Individual donor data are illustrated to demonstrate donor variability in these experiments.
Figure 5.
Figure 5.
Tat effects on microglial and astrocyte chemokine receptors expression. RPA analysis shows the constitutive expression of the CC chemokine receptors, CCR1, CCR2, CCR3, and CCR5. This expression is not altered by the addition of varying doses of Tat for 24 hours (A). Densitometric analyses show no significant changes in receptor expression after Tat treatment; however, there is a trend toward Tat inhibition of CCR2 and CCR5 after 50 and 100 ng/ml treatment of Tat (n = 3) (B). RPA analysis of astrocyte chemokine receptor mRNA expression shows no constitutive expression of C-C receptors and this is not altered by treatment with Tat (n = 2) (C).
Figure 6.
Figure 6.
Chemokine effects on chemokine expression by human fetal microglia. The ability of chemokines to induce chemokine production was analyzed. ELISA analysis of cell culture supernatants shows MIP-1α and MIP-1β to induce significantly (P ≤ 0.05) the expression of MIP-1α (A), MIP-1β (B), and MCP-1(C) after 24 hours of treatment (n = 6). Each symbol denotes a separate donor and is used to accurately demonstrate the variability in data obtained from individual donors in these experiments.
Figure 7.
Figure 7.
Astrocyte chemokine expression in response to chemokines. ELISA analysis of chemokine protein expression shows significant induction of MIP-1α by MIP-1β (100 ng/ml) after 24 hours of treatment (A), significant induction of MIP-1β after MIP-1α (100 ng/ml) treatment (B), and significant induction of MCP-1 by MIP-1α or MIP-1β (100 ng/ml) after 24 hours of treatment (n = 7) (C). Each symbol denotes a separate donor and is used to accurately reflect donor variability in these experiments.
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