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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 4

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S-CM downregulation of monocyte surface antigen expression. (A) Blood mo...
S-CM downregulation of monocyte surface antigen expression. (A) Blood monocytes cultured for 4 days in the absence or presence of S-CM, E-CM, or MNL-CM at the indicated concentrations were analyzed by FACS for HLA-DR, CD13, CD14, and CD16 (open histograms). Cells were also stained with FITC IgG1 and PE IgG2a irrelevant Abs (solid histograms). FACS insets show the flow-cytometric analysis of intestinal macrophages for the same surface marker. Data are from a representative experiment (n = 3). Electron micrograph inset shows a representative monocyte after 24-hour culture with S-CM (150 μg/ml total protein). (B) Blood monocytes incubated with S-CM (150 μg/ml total protein) and in the absence or presence of protease inhibitors, including trypsin, chymotrypsin, pronase, thermolysin, papain, and pancreas extract, as described in Methods, were analyzed by FACS as above.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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