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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

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 1

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Ultrastructure and purity of intestinal macrophages and blood monocytes....
Ultrastructure and purity of intestinal macrophages and blood monocytes. A representative intestinal macrophage and blood monocyte show typical eccentric nuclei, villous processes (especially on the intestinal macrophage), and in the macrophage, primary and secondary lysosomes and phagocytic vacuoles (magnification, ×10,000). FACS profiles for intestinal macrophages and blood monocytes show that both populations express the mononuclear phagocyte markers HLA-DR and CD13, but not markers for T cells (CD3), B cells (CD20), NK cells (CD69), or DCs (CD83). Insets show control cells stained with CD3 (PBLs), CD20 (PBLs), CD69 (PBLs), and CD83 (monocyte-derived DCs). Both populations also did not express CD33, CD34, or CD103, markers for bone marrow macrophage precursors, follicular DCs and intestinal lymphocytes, respectively.
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