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Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity
Lesley E. Smythies, … , Jan M. Orenstein, Phillip D. Smith
Lesley E. Smythies, … , Jan M. Orenstein, Phillip D. Smith
Published January 3, 2005
Citation Information: J Clin Invest. 2005;115(1):66-75. https://doi.org/10.1172/JCI19229.
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Article Immunology Article has an altmetric score of 13

Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity

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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), Fcα (CD89), Fcγ (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-β, and TNF-α, 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-β, 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

Lesley E. Smythies, Marty Sellers, Ronald H. Clements, Meg Mosteller-Barnum, Gang Meng, William H. Benjamin, Jan M. Orenstein, Phillip D. Smith

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Figure 6

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Phagocytic and bacteriocidal activity of blood monocytes and intestinal ...
Phagocytic and bacteriocidal activity of blood monocytes and intestinal macrophages. (A) Blood monocyte and intestinal macrophage phagocytosis in the absence or presence of S-CM. Phagocytosis was measured as the percentage of cells that contained FITC-labeled beads after 1-hour incubation. Values are mean + SD (n = 3). (B) Phagocytosis-induced cytokine production by blood monocytes and intestinal macrophages. Blood monocytes and intestinal macrophages were incubated with latex beads for 2 hours, washed, cultured for 24 hours, and the supernatants assayed for IL-1 (black bars), IL-6 (dark gray bars), TNF-α (light gray bars), and IL-8 (white bars). Values are mean + SD (n = 4). Inset: S-CM downregulation of phagocytosis-induced cytokine release by monocytes. Blood monocytes were incubated with latex beads in the absence or presence of increasing concentrations of S-CM, washed, and cultured for 24 hours in the same concentrations of S-CM. Culture supernatants were harvested and assayed for IL-1 and TNF-α. Values are mean + SD (n = 3). (C and D) Killing of Gram-negative bacteria by blood monocytes and intestinal macrophages. Intestinal macrophages, blood monocytes, and blood monocytes plus S-CM 500 μg/ml (2 × 105 cells/250 μl) were incubated with (C) S. typhimurium (8 × 106 CFU/ml) or (D) E. coli (4 × 106 CFU/ml), and intracellular killing was determined as described in Methods. The 3 populations of cells killed the vast majority of the bacteria within 30–60 minutes.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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