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

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), 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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S-CM TGF-β downregulates monocyte cytokine production. (A) S-CM induces ...
S-CM TGF-β downregulates monocyte cytokine production. (A) S-CM induces decreased TNF-α and increased TGF-β release by monocytes. Blood monocytes were incubated in the absence or presence of increasing concentrations of S-CM for 1 hour and then for an additional 24 hours with LPS (1 μg/ml). The harvested supernatants were analyzed for TNF-α and TGF-β protein. Values are mean + SD (n = 3). Parallel cultures of similarly treated monocytes (2 hours) were analyzed by RT-PCR for TNF-α and GAPDH mRNA. (B) TGF-β Abs block S-CM–induced downregulation of LPS-stimulated TNF-α release by monocytes. Blood monocytes were incubated with increasing concentrations of anti–TGF-β Abs and S-CM (150 μg/ml) and stimulated with LPS (1 μg/ml) for 24 hours. Supernatants were analyzed for TNF-α protein. Neither anti–TGF-β nor anti–IL-10 Abs (200 μg/ml each) in the absence of S-CM significantly affected monocyte production of TNF-α or IL-1. Values are mean + SD (n = 3). Parallel cultures were analyzed for TNF-α and GAPDH mRNA as in A.