Neurobiology of Aging 26 (2005) 363–372 Sex steroids, APOE genotype and the innate immune system Carol A. Colton ∗ , Candice M. Brown, Michael P. Vitek Division of Neurology, Box 2900, Bryan Research Bldg, Duke University Medical Center, Durham, NC 27710, USA Received 6 April 2004; received in revised form 5 August 2004; accepted 20 August 2004 Abstract Microglia are a primary cellular component of the CNS innate immune system. Their response to conserved pathogen motifs is inherent and leads to the release of cytoactive factors that impact surrounding neurons and glia. The microglial response is modified by the local tissue environment and by “global” factors such as gender. Exposure to estrogen and testosterone, in general, down regulate microglia and peripheral macrophage function, promoting an anti-inflammatory phenotype. Other global factors, however, can “override” the gender-based effects demonstrated by estrogen or testosterone. Apolipoprotein E (APOE) genotype and the expression of specific isoforms of apolipoprotein E differentially regulate microglial and peripheral macrophage function. Our studies have shown that the presence of the APOE4 gene, a known risk factor for AD and other neurodegenerative diseases, promotes a pro-inflammatory macrophage phenotype in neonatal microglia. However, in adult mice, the APOE genotype-specific effect depends on gender. Peritoneal macrophages from female adult APOE3 and APOE4 targeted replacement mice do not demonstrate an APOE genotype-specific response, whereas adult male APOE4 targeted replacement mice show enhanced macrophage responsiveness compared to adult male APOE3 mice. At least part of the altered macrophage response in APOE4 male mice may be due to differences in androgen receptor sensitivity to testosterone. These data re-enforce the concept that classical activation in macrophages has multiple levels of regulation, dictated by competing or synergistic factors and genotype. © 2004 Elsevier Inc. All rights reserved. Keywords: Neuroinflammation; Microglia; Macrophage; APOE4; Gender; Estrogen; Androgen; Alzheimer’s disease The innate immune system is an ancient, highly conserved system of defense against pathogens that is found in some form in most multicellular organisms. This system is charac- terized as the “first line of immune defense”, providing rapid detection, isolation and destruction of microbial and viral pathogens. The cells that fully participate in the innate im- mune response are derived from the mononuclear phagocyte Abbreviations: A, amyloid beta peptide; AD, Alzheimer’s disease; APOE, apolipoprotein E; APOE TR, apolipoprotein E targeted replacement; APP, amyloid precursor protein; AR, androgen receptor; c-fms, colony stim- ulating factor receptor gene; CSF, colony stimulating factor; CSF-R, colony stimulating factor receptor; E2, estrogen; ER, estrogen receptor alpha; ER, Estrogen receptor beta; HSP60, heat shock protein 60; IFN, inter- feron; IL-1, Interleukin 1; LPS, lipopolysaccharide; MPP, metalloprotein protease; MPS, mononuclear phagocyte system; NGF, nerve growth fac- tor; NO, nitric oxide; PAMP, pathogen associated molecular patterns; PIC, polyinosinic: polycytidylic acid; TNF, tumor necrosis factor- alpha; TLR, toll-like receptor; VIP, vasoactive intestinal polypeptide ∗ Corresponding author. Tel.: +1 919 668 2758; fax: +1 919 684 6514. E-mail address: glia01@aol.com (C.A. Colton). system (MPS), a family of cells that include hematopoietic progenitors, circulating monocytes and tissue macrophages [41]. MPS cells share many common features such as anti- gen presentation to primed T lymphocytes, but can be most readily distinguished by the expression of c-fms, the gene that encodes the colony stimulating factor 1 receptor (CSF- R) [41]. Growth and differentiation of MPS cells depends on lineage-specific cytokines such as colony stimulating factor (CSF). The microglia are the primary representative of the MPS in the CNS and reside within the parenchyma or in close approximation to cerebral blood vessels at the brain–blood vessel interface. However, astrocytes also participate in the CNS immune response [9,24,63]. In addition to presenting antigen, astrocytes produce cytoactive factors such as CSF and S100 beta that affect microglial function [34]. In turn, microglia release factors that influence astrocytes. A third cell type, the dendritic cells, also play a role in innate immu- nity. Dendritic cells are derived from the MPS and link the 0197-4580/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2004.08.001