title: Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity.
abstract: Intestinal macrophages, which are thought to orchestrate mucosal inflammatory responses, have received little investigative attention compared with macrophages from other tissues. Here we show that human intestinal macrophages do not express innate response receptors, including the receptors for LPS (CD14), Fcalpha (CD89), Fcgamma (CD64, CD32, CD16), CR3 (CD11b/CD18), and CR4 (CD11c/CD18); the growth factor receptors IL-2 (CD25) and IL-3 (CD123); and the integrin LFA-1 (CD11a/CD18). Moreover, resident intestinal macrophages also do not produce proinflammatory cytokines, including IL-1, IL-6, IL-10, IL-12, RANTES, TGF-beta, and TNF-alpha, in response to an array of inflammatory stimuli but retain avid phagocytic and bacteriocidal activity. Thus, intestinal macrophages are markedly distinct in phenotype and function from blood monocytes, although intestinal macrophages are derived from blood monocytes. To explain this paradox, we show that intestinal stromal cell-derived products downregulate both monocyte receptor expression and, via TGF-beta, cytokine production but not phagocytic or bacteriocidal activity, eliciting the phenotype and functional profile of intestinal macrophages. These findings indicate a mechanism in which blood monocytes recruited to the intestinal mucosa retain avid scavenger and host defense functions but acquire profound "inflammatory anergy," thereby promoting the absence of inflammation characteristic of normal intestinal mucosa despite the close proximity of immunostimulatory bacteria.
authors.affiliation: Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Lesley E
authors.initials: LE
authors.lastname: Smythies
authors.forename: Marty
authors.initials: M
authors.lastname: Sellers
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Clements
authors.forename: Meg
authors.initials: M
authors.lastname: Mosteller-Barnum
authors.forename: Gang
authors.initials: G
authors.lastname: Meng
authors.forename: William H
authors.initials: WH
authors.lastname: Benjamin
authors.forename: Jan M
authors.initials: JM
authors.lastname: Orenstein
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004926:Escherichia coli / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D007583:Jejunum / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D010587:Phagocytosis; D010641:Phenotype; D012486:Salmonella typhimurium / Q000276:immunology* / Q000502:physiology; D017154:Stromal Cells / Q000737:chemistry / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta