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Published online before print June 24, 2004
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in vitro: distinct roles of class A scavenger and Toll-like pattern recognition receptors in selective modulation of surface phenotype
Sir William Dunn School of Pathology, South Parks Road, Oxford, United Kingdom
1 Correspondence: Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK. E-mail: Christine.holt{at}path.ox.ac.uk
Innate and adaptive immune activation of macrophages (M
) by microorganisms and antigen-activated lymphoid cells, respectively, plays an important role in host defense and immunopathology. Antigen-presenting cells express a range of pattern recognition receptors including the class A types I and II scavenger receptors (SR-A) and Toll-like receptors (TLR). Recognition of microbial products by SR-A and TLR controls uptake, killing, altered gene expression, and the adaptive immune response; however, the contribution of each receptor and interplay with cytokine stimuli such as interferon-
(IFN-) are not defined. We used Neisseria meningitidis (NM), a potent activator of innate immunity, and IFN-, a prototypic T helper cell type 1 proinflammatory cytokine, to compare surface antigens, secretion of mediators, and receptor functions in elicited peritoneal M from wild-type and genetically modified mouse strains. We show that these stimuli regulate major histocompatibility complex type II (MHC-II) and costimulatory molecules differentially, as well as expression of the mannose receptor and of M receptor with collagenous structure (MARCO), a distinct SR-A, which provides a selective marker for innate activation. In combination, NM inhibited up-regulation of MHC-II by IFN- while priming enhanced release of tumor necrosis factor 
and nitric oxide. The SR-A contributes to phagocytosis of the organisms but not to their ability to induce CD80, CD86, and MARCO or to inhibit MHC-II. Conversely, studies with lipopolysaccharide (LPS)-deficient organisms and/or TLR-4 mutant mice showed that LPS and TLR-4 are at least partially required to induce CD80, CD86, and MARCO, but LPS is not required to inhibit MHC-II. These studies provide an experimental model and identify surface markers for analysis of innate and acquired immune activation of M.
Key Words: macrophages • cellular activation • cell-surface molecules • phagocytosis • bacterial infection
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