CD40-CD40L Interactions Induce Chemokine Expression by Human Microglia : Implications for Human Immunodeficiency Virus Encephalitis and Multiple Sclerosis

• Published in: The American journal of pathology Vol. 160; no. 2; pp. 559 - 567
• Main Authors: D'Aversa, Teresa G, Weidenheim, Karen M, Berman, Joan W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD ASIP 01-02-2002; American Society for Investigative Pathology
• Subjects: Adolescent; Adult; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - immunology; Antigens, Differentiation, Myelomonocytic - metabolism; Biological and medical sciences; Brain - pathology; Brain - physiopathology; CD40 Antigens - immunology; CD40 Antigens - metabolism; CD40 Ligand - immunology; CD40 Ligand - metabolism; CD40 Ligand - pharmacology; Cells, Cultured; Chemokines - genetics; Chemokines - immunology; Chemokines - metabolism; Child; Encephalitis, Viral - physiopathology; Female; HIV Infections - immunology; HIV Infections - physiopathology; Human viral diseases; Humans; Infant; Infectious diseases; Interferon-gamma - pharmacology; Male; Medical sciences; Microglia - drug effects; Microglia - immunology; Microglia - metabolism; Middle Aged; Mitogen-Activated Protein Kinases - metabolism; Multiple Sclerosis - immunology; Multiple Sclerosis - physiopathology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; Regular; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Human; Immunohistochemistry; Immunopathology; Encephalitis; Nervous system diseases; Multiple sclerosis; Ligand; Pathogenesis; AIDS; Immune deficiency; Cerebral disorder; Inflammatory disease; Microglia; Infection; Chemokine; Pathology; Viral disease; Central nervous system disease; Molecular biology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)64875-4

CD40 is a protein on microglia that is up-regulated with interferon (IFN)-gamma and is engaged by CD40L, found on CD4+ T cells, B cells, and monocytes. These interactions may be important in central nervous system inflammatory diseases. Microglia have been shown to be a source of chemokines, whose expression plays a key role in central nervous system pathologies. We examined the expression of CD40 on microglia in human immunodeficiency virus (HIV) encephalitic brain, and the effects of CD40-CD40L interactions on the expression of chemokines by cultured microglia. We found significantly increased numbers of CD40-positive microglia in HIV-infected brain tissue. Treatment of cultured microglia with IFN-gamma and CD40L increased expression of several chemokines. IFN-gamma- and CD40L-induced MCP-1 protein was mediated by activation of the ERK1/2 MAPK pathway, and Western blot analysis demonstrated phosphorylation of ERK1/2 upon stimulation of microglia. In contrast, IFN-gamma- and CD40L-induced IP-10 protein production was mediated by the p38 MAPK pathway. Our data suggest a mechanism whereby CD40L+ cells can induce microglia to secrete chemokines, amplifying inflammatory processes seen in HIV encephalitis and multiple sclerosis, and implicate CD40-CD40L interactions as a target for interventional strategies.