Tissue-Specific Differentiation of Colonic Macrophages Requires TGFβ Receptor Mediated Signalling

Intestinal macrophages (mφ) form one of the largest populations of mφ in the body and are vital for the maintenance of gut homeostasis. They have several unique properties and are derived from local differentiation of classical Ly6Chi monocytes, but the factors driving this tissue-specific process are not understood. Here we have used global transcriptomic analysis to identify a unique homeostatic signature of mature colonic mφ that is acquired as they differentiate in the mucosa. By comparing the analogous monocyte differentiation process found in the dermis, we identify TGFβ as an indispensable part of monocyte differentiation in the intestine and show that it enables mφ to adapt precisely to the requirements of their environment. Importantly, TGFβR signaling on mφ has a crucial role in regulating the accumulation of monocytes in the mucosa, via mechanisms that are distinct from those used by IL10.

• Publication year

  2017

• Venue

  Mucosal Immunology

• Publication date

  2017-01-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/mi.2016.142PMID 28145440PMCID 5417360
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2016cited by this paper
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  2015cited by this paper
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  2015cited by this paper
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• Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

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• Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment.

  2014influential reference
• Tissue-specific signals control reversible program of localization and functional polarization of macrophages.

  2014cited by this paper
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  2014cited by this paper
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  2013influential reference
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
• Negative regulatory receptors of the IL-1 family.

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  2013cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2011cited by this paper
• TGF-β2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine.

  2011cited by this paper
• Loss of interleukin-10 or transforming growth factor β signaling in the human colon initiates a T-helper 1 response via distinct pathways.

  2011cited by this paper
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  2010cited by this paper
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  2010cited by this paper
• Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10.

  2010cited by this paper
• TGF-β Is Required To Maintain the Pool of Immature Langerhans Cells in the Epidermis

  2010cited by this paper
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  2010cited by this paper
• Intestinal lamina propria dendritic cell subsets have different origin and functions.

  2009cited by this paper
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  2007cited by this paper
• Ulcerative colitis and autoimmunity induced by loss of myeloid αv integrins

  2007cited by this paper
• Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins.

  2007cited by this paper
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  2006cited by this paper
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  2005cited by this paper
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  2004cited by this paper
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  2004cited by this paper
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  2001cited by this paper
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  2000cited by this paper
• Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice.

  1997cited by this paper
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  1985cited by this paper

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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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