scispace - formally typeset
Search or ask a question
Journal Article•DOI•

The role of the macrophage in sentinel responses in intestinal immunity.

Shehzad Z. Sheikh1, Scott E. Plevy1•
University of North Carolina at Chapel Hill1
01 Nov 2010-Current Opinion in Gastroenterology (NIH Public Access)-Vol. 26, Iss: 6, pp 578-582
TL;DR: Converging human genetic and functional findings suggest that dysregulation of macrophage-specific immune responses against an otherwise harmless enteric microbiota are key factors in the pathogenesis of inflammatory bowel disease.
Abstract: Purpose of review The purpose of this review is to highlight macrophages as central mediators of intestinal immune homeostasis and inflammation. Recent findings We review recent developments elucidating distinct phenotypic adaptations in intestinal macrophages that determine their functional role in a microbe-rich environment. The involvement of intestinal macrophages in the pathogenesis of inflammatory bowel disease is also discussed. Summary Intestinal macrophages represent the largest pool of tissue macrophages in the human body and a critical interface with the enteric microbiota. In normal physiology, luminal microbes breach the intestinal epithelial barrier and gain access to the lamina propria. Bacteria are efficiently phagocytosed by macrophages strategically located underneath the epithelium. The importance of functional adaptations of macrophages to perform their role in this unique environment is best illustrated by failure of these mechanisms during the development of chronic inflammatory bowel diseases. Compared with monocytes or macrophages from any other organ, intestinal macrophages express different phenotypic markers, efficiently eradicate intracellular bacteria, but do not mount potent inflammatory responses. Converging human genetic and functional findings suggest that dysregulation of macrophage-specific immune responses against an otherwise harmless enteric microbiota are key factors in the pathogenesis of inflammatory bowel disease.

Summary (2 min read)

Jump to: [Introduction] – [Current views on macrophage development and biology] – [Microbial recognition and eradication by macrophages] – [Distinct properties of resident intestinal macrophages] – [Regulation of intestinal macrophage phenotype and function] – [Lessons learned from murine models of experimental colitis] – [Intestinal macrophages in human inflammatory bowel disease] and [Conclusion]

Introduction

  • The innate immune system contributes to the functional integrity of the intestinal mucosa in health and disease through monitoring of luminal contents, particularly the enteric microbiota.
  • Key participants in intestinal innate immune defenses are macrophages.
  • Innate responses are rapid and directed toward conserved patterns of carbohydrate and lipid structures on infectious agents [pathogen-associated molecular patterns, or ] recognized by germ line-encoded pattern recognition receptors, toll-like receptors (TLRs) and nod-like receptors (NLRs) [1] .
  • Engagement of these receptors stimulates signaling cascades that include nuclear factor-κB, serine/threonine protein kinase (AKT)/ phosphoinositide-3'-kinase, and mitogen-activated protein kinase pathways [2] .
  • In IBD, following an inflammatory signal, circulating monocytes migrate to the intestinal mucosa and, unlike resident macrophages, are capable of a rapid response to luminal microbial triggers [5] .

Current views on macrophage development and biology

  • A common myeloid progenitor cell gives rise to monocytes, which are released from the bone marrow into the bloodstream.
  • Innate and adaptive signals can then influence macrophage physiology, and these alterations allow macrophages to participate in homeostatic processes, such as tissue remodeling, wound healing, and host defense.
  • Phenotypically, M1 macrophages are identified by the expression of inducible nitric oxide synthase, C-C motif chemokine 15 (CCL15) and 20 (CCL20), γ-interferon-induced monokine 9 (CXCL9) and 10 (CXCL10) [6] .
  • They are also mediators of pathology that occurs during chronic inflammatory disorders, including IBD.
  • Production of IL-10, TGF-β, PGE 2 , and the ability to suppress IL-12 production are hallmarks of regulatory macrophages [9] .

Microbial recognition and eradication by macrophages

  • Macrophages are essential for the phagocytosis and clearance of enteric bacteria that breach the intestinal epithelial barrier [11] .
  • Autophagy and phagolysosomal function have emerged as central components of the macrophage machinery to eradicate intracellular bacteria [12] .
  • Moreover, the Crohn's disease susceptibility gene N has recently been linked to autophagy [13 ].
  • Autophagy, directly translated as 'self-eating', is a process whereby cells digest their own organelles or cytoplasm, allowing survival during periods of nutrient deprivation.
  • A fundamental question in mucosal immunity is how mucosal innate host defense distinguishes pathogenic from resident microbes.

Distinct properties of resident intestinal macrophages

  • The local intestinal microenvironment substantially influences the differentiation of macrophages.
  • Similarly, most intestinal macrophages lack the integrin α2β1 (lymphocyte functionassociated antigen-1 and CD11a/CD18) [20, 21] .
  • Upregulation of several cell surface molecules (C40, CD86, and CD32) also prolongs survival of TREM-1-positive myeloid cells [22] .
  • This is in sharp contrast to other tissue macrophages and blood monocytes.

Regulation of intestinal macrophage phenotype and function

  • The local intestinal milieu shapes the function and phenotype of intestinal macrophages.
  • Blocking TGF-β reverses these effects [21] .
  • Monocytes cultured with multicellular spheroids of intestinal epithelial cells acquire an intestinal macrophage phenotype, characterized by reduced CD14 and reduced lipopolysaccharides-stimulated IL-1β expression [30] .
  • Retinoic acid directly influences the development and effector functions of intestinal macrophages.
  • These studies emphasize the complexity of the intestinal APC network that differentially regulates mucosal immune responses.

Lessons learned from murine models of experimental colitis

  • Murine models of experimental colitis have demonstrated the importance of macrophage regulation for maintaining local tissue homeostasis.
  • Depletion of macrophages in IL-10 −/− mice prevents the development of colitis [35] .
  • T-cell phenotype characterized by the production of the cytokine IL-17, denoted Th17 cells.
  • Indeed, IFN-γ, the signature Th1 cytokine induced by IL-12, and IL-10 were both recently shown to inhibit IL-23 in lamina propria macrophages [36 ].
  • Treg cells have been shown to suppress the activity of Th1 and Th17 cells in inflamed tissues [1] .

Intestinal macrophages in human inflammatory bowel disease

  • Intestinal inflammation in the human IBDs, Crohn's disease and ulcerative colitis, results from an inappropriately directed inflammatory response to the enteric microbiota in a genetically susceptible host.
  • Furthermore, subsets of intestinal macrophages express TLR2, TLR4, CD89, and TREM-1 at the site of intestinal inflammation [19] .
  • CD14 expressing macrophages (CD14+) infiltrating the mucosa in IBD produce larger amounts of IL-12, IL-23, and TNF compared with intestinal macrophages from healthy controls.
  • These CD14+ macrophages produce IFN-γ that further triggers abnormal macrophage differentiation with an IL-23-hyperproducing phenotype [35] .
  • Coupled with reduced secretion, these findings indicate that accelerated intracellular defects in genes encoding proteins involved in vesicle trafficking may result in an abnormal proportion of cytokines being routed to lysosomes and degraded rather than being released through the normal secretory pathway [7 ].

Conclusion

  • Until recently, research on the pathogenesis of IBD has focused on effector mechanisms of the adaptive immune system.
  • Detailed mechanisms of how intestinal macrophages functionally differentiate and participate in the pathogenesis of IBD may suggest specific strategies that target induction of macrophage specific regulatory responses and prevent chronic inflammation.
  • Vital to the development of such therapies is an intricate knowledge about the monocyte/ macrophage lineage relationships, differential homing capacities, and the effects of the local cytokine milieu on macrophage function and phenotype, and the plasticity of intestinal macrophage subsets.

Did you find this useful? Give us your feedback

Content maybe subject to copyright    Report

The role of the macrophage in sentinel responses in intestinal
immunity
Shehzad Z. Sheikh and Scott E. Plevy
Department of Medicine, Microbiology and Immunology, University of North Carolina at Chapel
Hill School of Medicine, Chapel Hill, North Carolina, USA
Abstract
Purpose of review—The purpose of this review is to highlight macrophages as central
mediators of intestinal immune homeostasis and inflammation.
Recent findings—We review recent developments elucidating distinct phenotypic adaptations
in intestinal macrophages that determine their functional role in a microbe-rich environment. The
involvement of intestinal macrophages in the pathogenesis of inflammatory bowel disease is also
discussed.
Summary—Intestinal macrophages represent the largest pool of tissue macrophages in the
human body and a critical interface with the enteric microbiota. In normal physiology, luminal
microbes breach the intestinal epithelial barrier and gain access to the lamina propria. Bacteria are
efficiently phagocytosed by macrophages strategically located underneath the epithelium. The
importance of functional adaptations of macrophages to perform their role in this unique
environment is best illustrated by failure of these mechanisms during the development of chronic
inflammatory bowel diseases. Compared with monocytes or macrophages from any other organ,
intestinal macrophages express different phenotypic markers, efficiently eradicate intracellular
bacteria, but do not mount potent inflammatory responses. Converging human genetic and
functional findings suggest that dysregulation of macrophage-specific immune responses against
an otherwise harmless enteric microbiota are key factors in the pathogenesis of inflammatory
bowel disease.
Keywords
inflammatory bowel disease; innate immunity; macrophage
Introduction
The innate immune system contributes to the functional integrity of the intestinal mucosa in
health and disease through monitoring of luminal contents, particularly the enteric
microbiota. Key participants in intestinal innate immune defenses are macrophages. Innate
responses are rapid and directed toward conserved patterns of carbohydrate and lipid
structures on infectious agents [pathogen-associated molecular patterns, or (PAMPs)]
recognized by germ line-encoded pattern recognition receptors, toll-like receptors (TLRs)
and nod-like receptors (NLRs) [1]. Engagement of these receptors stimulates signaling
cascades that include nuclear factor-κB, serine/threonine protein kinase (AKT)/
© 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Correspondence to Dr Scott E. Plevy, MD, Department of Medicine, Microbiology and Immunology, University of North Carolina at
Chapel Hill School of Medicine, CB 7032, 7341c MBRB, 103 Mason, Farm Road, Chapel Hill, NC 27599, USA, Tel: +1 919 966
4405; fax: +1 919 843 2585; scott_plevy@med.unc.edu.
NIH Public Access
Author Manuscript
Curr Opin Gastroenterol. Author manuscript; available in PMC 2011 November 13.
Published in final edited form as:
Curr Opin Gastroenterol
. 2010 November ; 26(6): 578–582. doi:10.1097/MOG.0b013e32833d4b71.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
phosphoinositide-3’-kinase, and mitogen-activated protein kinase pathways [2]. Mutations
in TLRs and NLRs have been associated with inflammatory bowel disease (IBD),
suggesting that this innate immune detection system is key for regulating mucosal
homeostasis [3].
The intestinal innate immune system is in a default state of hyporesponsiveness. Intestinal
macrophages show attenuated proliferation and chemotactic activity in response to microbial
ligands and cytokines/chemokines despite possessing the molecular mechanisms to elaborate
strong phagocytic and bactericidal responses [4]. However, in IBD, following an
inflammatory signal, circulating monocytes migrate to the intestinal mucosa and, unlike
resident macrophages, are capable of a rapid response to luminal microbial triggers [5].
Current views on macrophage development and biology
A common myeloid progenitor cell gives rise to monocytes, which are released from the
bone marrow into the bloodstream. These peripheral blood monocytes migrate to tissues
under the steady state or in response to inflammation. Innate and adaptive signals can then
influence macrophage physiology, and these alterations allow macrophages to participate in
homeostatic processes, such as tissue remodeling, wound healing, and host defense.
Macrophages also have remarkable plasticity that allows them to efficiently respond to
environmental signals and change their functional characteristics.
Macrophages have been somewhat simplistically classified as M1 [high interleukin (IL)-12
and low IL-10 producing] macrophages and M2 macrophages (low IL-12 and high IL-10
producing). M1 or classically activated macrophages develop during cell-mediated immune
responses requiring both interferon (IFN)-γ and tumor necrosis factor (TNF). Classically
activated macrophages form an integral component of host defense through production of
inflammatory cytokines such as IL-1, IL-6, IL-12, and IL-23 [6]. Phenotypically, M1
macrophages are identified by the expression of inducible nitric oxide synthase, C-C motif
chemokine 15 (CCL15) and 20 (CCL20), γ-interferon-induced monokine 9 (CXCL9) and 10
(CXCL10) [6]. M1 macrophages are essential for eradication of intracellular
microorganisms [7
•
]. However, they are also mediators of pathology that occurs during
chronic inflammatory disorders, including IBD.
M2 or alternatively activated macrophages represent a wide array of macrophage
phenotypes [6]. This spectrum includes macrophages with wound healing and regulatory
properties [6]. In response to injury, early increases in IL-4 and/or IL-13 rapidly convert
resident macrophages into a population of cells programmed to promote wound healing
through production of extracellular matrix [8]. Regulatory macrophages that arise during
innate or adaptive immune responses, under the influence of IL-10 and transforming growth
factor (TGF)-β, dampen the immune response and limit inflammation [6]. Production of
IL-10, TGF-β, PGE
2
, and the ability to suppress IL-12 production are hallmarks of
regulatory macrophages [9]. Phenotypically, M2 macrophages are identified by the
expression of arginase 1, chitinase-like protein that can bind to extracellular matrix, and
found in inflammatory zone 1 [10].
Microbial recognition and eradication by macrophages
Macrophages are essential for the phagocytosis and clearance of enteric bacteria that breach
the intestinal epithelial barrier [11]. Autophagy and phagolysosomal function have emerged
as central components of the macrophage machinery to eradicate intracellular bacteria [12].
Indeed, the importance of microbicidal pathways in the pathogenesis of IBD is highlighted
by the discovery that synonymous single nucleotide polymorphisms in the autophagocytic
genes ATG16L1 and IRGM and the phagosomal gene NCF4 are associated with enhanced
Sheikh and Plevy Page 2
Curr Opin Gastroenterol. Author manuscript; available in PMC 2011 November 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
risk for IBD [1,12]. Moreover, the Crohn’s disease susceptibility gene N has recently been
linked to autophagy [13
•
]. Autophagy, directly translated as ‘self-eating’, is a process
whereby cells digest their own organelles or cytoplasm, allowing survival during periods of
nutrient deprivation. Importantly, autophagy is required to protect against bacteria that
invade cells, and recent functional analyses suggest that Crohn’s disease-associated
autophagy mutations may impair the ability of cells to eradicate intracellular bacteria
[14,15]. Signaling through NLRs and TLRs can lead to autophagosome formation [13
•
,16].
During autophagy, cytoplasmic material including organelles, protein aggregates, or bacteria
is sequestered into double membrane-bound autophagosomes that subsequently fuse with
endosomes and lysosomes to form autolysosomes, where lysosomal degradation occurs.
Autophagy also has a major role in antigen presentation, with fusion of autophagosomes
with multivesicular major histocompatibility complex (MHC) class II loading compartments
in macrophages [17].
A fundamental question in mucosal immunity is how mucosal innate host defense
distinguishes pathogenic from resident microbes. It is not known how pattern recognition
receptors such as NLRs and TLRs differentiate conserved molecular patterns on pathogenic
and commensal bacteria, nor is it known how this recognition process may be altered in
IBD.
Distinct properties of resident intestinal macrophages
The local intestinal microenvironment substantially influences the differentiation of
macrophages. Intestinal macrophages express high levels of MHC class II and the myeloid
marker aminopeptidase N (CD13), similarly to blood monocytes (Table 1) [18-26].
However, in contrast to their progenitor cells, resident monocytes, intestinal macrophages do
not function as professional antigen-presenting cells (APC) owing to their low cell surface
expression of the costimulatory molecules CD40, CD80, and CD86 [20]. They also lack the
Fc receptors for immunoglobulin A (CD89) and for immunoglobulin G (CD16, CD32, and
CD64) and the complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18).
Similarly, most intestinal macrophages lack the integrin α2β1 (lymphocyte function-
associated antigen-1 and CD11a/CD18) [20,21]. These receptors for the Fc and complement
family members on macrophages mediate cellular activation, secretion of proinflammatory
cytokines (TNF, IL-1β, IL-6, and IL-12) and drive adaptive immune responses. Intestinal
macrophages also lack the triggering receptor expressed on myeloid cells-1 (TREM-1), an
efficient amplifier of acute and chronic inflammatory reactions that is expressed on most
monocytes and macrophages in secondary lymphoid organs [22]. Engagement of TREM-1
on TREM-1-positive macrophages leads to enhanced TNF, IL-1β, and IL-6 secretion.
Upregulation of several cell surface molecules (C40, CD86, and CD32) also prolongs
survival of TREM-1-positive myeloid cells [22].
The selective absence of these receptors on intestinal macrophages has functional
implications in the maintenance of immune homeostasis. Intestinal macrophages under
physiological conditions are refractory to the induction of inflammatory cytokines by
PAMPs, cytokines (e.g., TNF, IFN-γ), and phagocytosis of necrotic cells [4]. This is in sharp
contrast to other tissue macrophages and blood monocytes. Intestinal epithelial cells,
subepithelial myofibroblasts, fibroblasts, lamina propria lymphocytes, and intraepithelial
lymphocytes also produce soluble factors, particularly TGF-β and IL-10, which determine
the functional properties of intestinal macrophages [27,28]. However, these adaptations
made by intestinal macrophages do not impair phagocytic activity. Intestinal macrophages
are highly effective at killing phagocytosed enteric bacteria such as Salmonella typhimurium
and Escherichia coli [21].
Sheikh and Plevy Page 3
Curr Opin Gastroenterol. Author manuscript; available in PMC 2011 November 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Regulation of intestinal macrophage phenotype and function
The local intestinal milieu shapes the function and phenotype of intestinal macrophages.
Blood monocytes treated with intestinal stromal cell-conditioned media rich in TGF-β
acquire a tolerized state with reduced expression of innate immune receptors and increased
phagocytotic activity, similar to intestinal macrophages. Blocking TGF-β reverses these
effects [21]. Similarly, IL-10, produced under physiological conditions in the intestinal
lamina propria, directly dampens macrophage function and upregulates TGF-β production in
multiple cell types [29]. Interestingly, monocytes cultured in the presence of TGF-β alone or
in combination with IL-10 do not acquire an intestinal macrophage phenotype [22].
However, monocytes cultured with multicellular spheroids of intestinal epithelial cells
acquire an intestinal macrophage phenotype, characterized by reduced CD14 and reduced
lipopolysaccharides-stimulated IL-1β expression [30].
Macrophages also maintain intestinal immune homeostasis through the generation of anergic
and/ or regulatory T cells in the intestine, and fine tuning adaptive immune responses by
altering the Th1/Th2/Th17 balance [31]. Retinoic acid directly influences the development
and effector functions of intestinal macrophages. A population of CD11b
+
F4/80
+
CD11c
−
intestinal macrophages that constitutively produce high levels of IL-10 express high levels
of Aldh1a1 and Aldh1a2, retinol dehydrogenases that convert retinol into retinoic acid, and
induce T-regulatory cells [32,33]. These macrophages convert naïve CD4
+
T cells to Foxp3
+
T cells in vitro in the presence of exogenous TGF-β via a mechanism dependent on both
IL-10 and Aldh1a1 and Aldh1a2 [33]. Importantly, not all intestinal APCs induce T-
regulatory cells. CD11c
+
CD11b
+
subset of dendritic cells in the lamina propria induces
robust Th17 responses [33]. These studies emphasize the complexity of the intestinal APC
network that differentially regulates mucosal immune responses.
Lessons learned from murine models of experimental colitis
Murine models of experimental colitis have demonstrated the importance of macrophage
regulation for maintaining local tissue homeostasis. Selective disruption of Stat3 leads to
impaired IL-10 signaling in macrophages and consequently leads to the development of
colitis [34]. Similarly, IL-10
−/−
mice spontaneously develop colitis as a consequence of the
preferential macrophage differentiation into proinflammatory subsets that produce large
amounts of IL-12 and IL-23 [35]. Depletion of macrophages in IL-10
−/−
mice prevents the
development of colitis [35].
Of the inflammatory genes induced in macrophages, IL-23 has been strongly implicated in
the pathogenesis of murine and human IBD [3]. IL-23 promotes a distinct CD4
+
T-cell
phenotype characterized by the production of the cytokine IL-17, denoted Th17 cells. IL-23
enhances Th17 function and survival by acting on differentiated Th17 cells that express the
IL-23 receptor. Indeed, IFN-γ, the signature Th1 cytokine induced by IL-12, and IL-10 were
both recently shown to inhibit IL-23 in lamina propria macrophages [36
•
]. As an illustration
of the functional adaptation of intestinal macrophages to their local environment, murine
colonic macrophages produce large amounts of IL-10 after encountering the enteric
microbiota [35]. In the context of adaptive immune responses, IFN-γ has been considered to
be a proinflammatory cytokine, driving Th1 responses. However, the enteric microbiota
transiently induces IFN-γ expression in the colon of wild type germfree mice colonized with
the enteric microbiota, which in turn attenuated IL-23 in macrophages, suggesting that local
macrophage-specific regulatory check points are vital in maintaining immune homeostasis
[36
•
].
The importance of intestinal macrophages in maintaining adaptive immune homeostasis was
recently highlighted in studies showing that IL-10 secreted from resident intestinal
Sheikh and Plevy Page 4
Curr Opin Gastroenterol. Author manuscript; available in PMC 2011 November 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
macrophages acts in a paracrine manner on regulatory T (Treg) cells to maintain Foxp3
expression [37
•
]. These Foxp3 expressing Treg cells have been shown to suppress the
activity of Th1 and Th17 cells in inflamed tissues [1].
Intestinal macrophages in human inflammatory bowel disease
Intestinal inflammation in the human IBDs, Crohn’s disease and ulcerative colitis, results
from an inappropriately directed inflammatory response to the enteric microbiota in a
genetically susceptible host. Genome wide association studies have identified IBD
susceptibility genes that affect barrier function and innate and adaptive immune responses in
the intestine. Genetic variants that confer Crohn’s disease risk highlight the importance of
innate immunity, including NOD2, NCX5, IRGM, and ATG16L1 [3].
In patients with active IBD, macrophage numbers are increased in inflamed intestinal
mucosa [1]. Many of these macrophages display a different phenotypic and functional
profile than under homeostatic conditions. Macrophages in the inflamed intestine express
functional T cell costimulatory molecules such as CD40, CD80, and CD86 [18].
Furthermore, subsets of intestinal macrophages express TLR2, TLR4, CD89, and TREM-1
at the site of intestinal inflammation [19]. Similarly, a high proportion of the macrophages
from patients with IBD express CD14 [20,24]. CD14 expressing macrophages (CD14+)
infiltrating the mucosa in IBD produce larger amounts of IL-12, IL-23, and TNF compared
with intestinal macrophages from healthy controls. These CD14+ macrophages produce
IFN-γ that further triggers abnormal macrophage differentiation with an IL-23-hyper-
producing phenotype [35]. In an inflammatory milieu, the close proximity of subepithelial
macrophages to the intestinal microbiota results in an excessive activation of the mucosal
immune system [35]. CD14+ intestinal macrophages from Crohn’s disease patients respond
vigorously to in-vitro microbial stimulation with production of abundant TNF, IL-12, and
IL-23, compared with CD14− intestinal macrophages [24]. CD14+ intestinal macrophages
also express TREM-1. TREM-1 triggers the synthesis and secretion of inflammatory factors
including IL-1β, monocyte chemotactic protein-1 (MCP-1), IL-6, and IL-8 [5]. Macrophages
are also the main source of TNF during the pathogenesis of IBD. The striking clinical
benefit of TNF-targeted monoclonal antibody therapies may be attributed to the cell-
depleting effects, including the removal of TNF membrane bound expressing macrophages
[38].
An impaired ability to eradicate intracellular pathogens by macrophages in IBD may also be
secondary to their inability to secrete proinflammatory cytokines in response to bacteria or
TLR agonists. Provocatively, it has been speculated that, despite normal levels and stability
of cytokine mRNA, intracellular levels of TNF are abnormally low in macrophages from
Crohn’s disease patients. Coupled with reduced secretion, these findings indicate that
accelerated intracellular defects in genes encoding proteins involved in vesicle trafficking
may result in an abnormal proportion of cytokines being routed to lysosomes and degraded
rather than being released through the normal secretory pathway [7
•
].
The concept that macrophages from patients with IBD display distinct functional
characteristics was further supported by studies demonstrating mutations in genes encoding
the IL-10 receptor (IL-10R) subunit proteins IIL10RA and IL10RB in patients with early-
onset enterocolitis [39
••
]. Increased secretion of TNF, macrophage inflammatory protein-1
(MIP1)α, MIP1β, MCP-1 and chemokine (C-C motif) ligand 5 (RANTES), and failure to
downregulate inflammatory cytokine expression by IL-10 in peripheral blood monocytes
from patients who were deficient in IL-10R subunit proteins, again demonstrate altered
macrophage responses that may underlie IBD pathogenesis. Interestingly, in this study,
Sheikh and Plevy Page 5
Curr Opin Gastroenterol. Author manuscript; available in PMC 2011 November 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Citations
More filters
Journal Article•DOI•
Pulmonary Macrophage Subpopulations in the Induction and Resolution of Acute Lung Injury

[...]

Laura K. Johnston1, Cliff Rims1, Sean E. Gill1, John K. McGuire2, Anne M. Manicone1 •
University of Washington1, Boston Children's Hospital2
29 Nov 2012-American Journal of Respiratory Cell and Molecular Biology
TL;DR: The presence and evolution of distinct macrophage subsets in the lung that serve specific niches in regulating the inflammatory response and its resolution are indicated and Alterations in the balance and function of these subpopulations could lead to nonresolving acute lung injury.
Abstract: Macrophages are key orchestrators of the inflammatory and repair responses in the lung, and the diversity of their function is indicated by their polarized states and distinct subpopulations and localization in the lung. Here, we characterized the pulmonary macrophage populations in the interstitial and alveolar compartments during the induction and resolution of acute lung injury induced by Pseudomonas aeruginosa infection. We identified macrophage subpopulations and polarity according to FACS analysis of cell surface protein markers, combined with cell sorting for gene expression using real-time PCR. With these techniques, we validated a novel, alternatively activated (M2) marker (transferrin receptor), and we described three interstitial and alveolar macrophage subpopulations in the lung whose distribution and functional state evolved from the induction to resolution phases of lung injury. Together, these findings indicate the presence and evolution of distinct macrophage subsets in the lung that serve specific niches in regulating the inflammatory response and its resolution. Alterations in the balance and function of these subpopulations could lead to nonresolving acute lung injury.

258 citations

Cites background from "The role of the macrophage in senti..."

  • ...IL-10–producing macrophages have been described in other tissues, such as the intestine, and the intestinal milieu was proposed to require antiinflammatory macrophage programming to limit overexuberant inflammatory responses in the gut (26)....

    [...]

Journal Article•DOI•
The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis.

[...]

Michele Biagioli1, Adriana Carino1, Sabrina Cipriani1, Daniela Francisci1, Silvia Marchianò1, Paolo Scarpelli1, Daniele Sorcini1, Angela Zampella2, Stefano Fiorucci1 •
University of Perugia1, University of Naples Federico II2
15 Jul 2017-Journal of Immunology
TL;DR: It is demonstrated that GPBAR1 gene ablation enhanced the recruitment of classically activated macrophages in the colonic lamina propria and worsened the severity of inflammation, and its activation promotes a IL-10–dependent shift toward an alternatively activated phenotype.
Abstract: GPBAR1 (TGR5 or M-BAR) is a G protein-coupled receptor for secondary bile acids that is highly expressed in monocytes/macrophages. In this study, we aimed to determine the role of GPBAR1 in mediating leukocyte trafficking in chemically induced models of colitis and investigate the therapeutic potential of BAR501, a small molecule agonist for GPBAR1. These studies demonstrated that GPBAR1 gene ablation enhanced the recruitment of classically activated macrophages in the colonic lamina propria and worsened the severity of inflammation. In contrast, GPBAR1 activation by BAR501 reversed intestinal inflammation in the trinitrobenzenesulfonic acid and oxazolone models by reducing the trafficking of Ly6C+ monocytes from blood to intestinal mucosa. Exposure to BAR501 shifted intestinal macrophages from a classically activated (CD11b+, CCR7+, F4/80-) to an alternatively activated (CD11b+, CCR7-, F4/80+) phenotype, reduced the expression of inflammatory genes (TNF-α, IFN-γ, IL-1β, IL-6, and CCL2 mRNAs), and attenuated the wasting syndrome and severity of colitis (≈70% reduction in the Colitis Disease Activity Index). The protective effect was lost in Gpbar1-/- mice. Exposure to BAR501 increased the colonic expression of IL-10 and TGF-β mRNAs and the percentage of CD4+/Foxp3+ cells. The beneficial effects of BAR501 were lost in Il-10-/- mice. In a macrophage cell line, regulation of IL-10 by BAR501 was GPBAR1 dependent and was mediated by the recruitment of CREB to its responsive element in the IL-10 promoter. In conclusion, GPBAR1 is expressed in circulating monocytes and colonic macrophages, and its activation promotes a IL-10-dependent shift toward an alternatively activated phenotype. The targeting of GPBAR1 may offer therapeutic options in inflammatory bowel diseases.

177 citations

Cites background from "The role of the macrophage in senti..."

  • ...display an anti-inflammatory phenotype, and it is thought that a wide transition between the two phenotypes exists (17, 18)....

    [...]

Journal Article•DOI•
Hypoxia, Metabolism and Immune Cell Function

[...]

Ewelina Krzywinska1, Christian Stockmann1, Christian Stockmann2•
French Institute of Health and Medical Research1, University of Zurich2
15 May 2018-Biomedicines
TL;DR: The role of HIFs in the function of innate and adaptive immune cells inHypoxia, with a focus on how hypoxia modulates immunometabolism, is discussed.
Abstract: Hypoxia is a hallmark of inflamed, infected or damaged tissue, and the adaptation to inadequate tissue oxygenation is regulated by hypoxia-inducible factors (HIFs). HIFs are key mediators of the cellular response to hypoxia, but they are also associated with pathological stress such as inflammation, bacteriological infection or cancer. In addition, HIFs are central regulators of many innate and adaptive immunological functions, including migration, antigen presentation, production of cytokines and antimicrobial peptides, phagocytosis as well as cellular metabolic reprogramming. A characteristic feature of immune cells is their ability to infiltrate and operate in tissues with low level of nutrients and oxygen. The objective of this article is to discuss the role of HIFs in the function of innate and adaptive immune cells in hypoxia, with a focus on how hypoxia modulates immunometabolism.

119 citations

Additional excerpts

  • ...M2 macrophages produce arginase-1 (Arg-1), Fizz-1, chitinase-like protein 3 and IL10 [123,124]....

    [...]

Journal Article•DOI•
Cells, cytokines and inflammatory bowel disease: a clinical perspective

[...]

Ian C. Roberts-Thomson1, James Fon1, Wendy Uylaki1, Adrian G. Cummins1, Simon C. Barry1 •
Boston Children's Hospital1
01 Dec 2011-Expert Review of Gastroenterology & Hepatology
TL;DR: The inflammatory infiltrate in both disorders and the cytokine profiles in intestinal mucosa and peripheral blood are examined to examine the identification, activation and function of subsets of inflammatory cells, as well as new ways to terminate the inflammatory response.
Abstract: Ulcerative colitis and Crohn’s disease are chronic inflammatory disorders of the GI tract. Although the disorders can usually be distinguished on clinical and pathological criteria, there are similarities in natural history and response to therapy. The purpose of this article is to examine the inflammatory infiltrate in both disorders and the cytokine profiles in intestinal mucosa and peripheral blood. For both disorders, the predominant cells in inflamed mucosa are neutrophils and lymphocytes positive for CD4. There are also increases in the number of B cells, macrophages, dendritic cells, plasma cells, eosinophils and perhaps mast cells. Cytokine levels and cytokine expression are also similar for both disorders, with increases in TNF-α and IFN-γ consistent with a Th1 response. As inflammation occurs in a microbial environment, one possibility is that the nature of the inflammatory response is largely independent of initiating factors. One concept that might be useful is that of initiating cells and cyt...

100 citations

Journal Article•DOI•
NFIL3 Is a Regulator of IL-12 p40 in Macrophages and Mucosal Immunity

[...]

Taku Kobayashi1, Katsuyoshi Matsuoka1, Shehzad Z. Sheikh1, Houda Z. Elloumi1, Nobuhiko Kamada2, Tadakazu Hisamatsu2, Jonathan J. Hansen1, Kevin R. Doty3, Scott D. Pope3, Stephen T. Smale3, Toshifumi Hibi2, Paul B. Rothman4, Masaki Kashiwada4, Scott E. Plevy1 •
University of North Carolina at Chapel Hill1, Keio University2, University of California, Los Angeles3, University of Iowa4
15 Apr 2011-Journal of Immunology
TL;DR: In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota.
Abstract: Regulation of innate inflammatory responses against the enteric microbiota is essential for the maintenance of intestinal homeostasis. Key participants in innate defenses are macrophages. In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota. Exposure to commensal bacteria and bacterial products induced NFIL3 in cultured macrophages and in vivo. The Il12b promoter has a putative DNA-binding element for NFIL3. Basal and LPS-activated NFIL3 binding to this site was confirmed by chromatin immunoprecipitation. LPS-induced Il12b promoter activity was inhibited by NFIL3 expression and augmented by NFIL3-short hairpin RNA in an Il12b-bacterial artificial chromosome-GFP reporter macrophage line. Il12b inhibition by NFIL3 does not require IL-10 expression, but a C-terminal minimal repression domain is necessary. Furthermore, colonic CD11b+ lamina propria mononuclear cells from Nfil3−/− mice spontaneously expressed Il12b mRNA. Importantly, lower expression of NFIL3 was observed in CD14+ lamina propria mononuclear cells from Crohn’s disease and ulcerative colitis patients compared with control subjects. Likewise, no induction of Nfil3 was observed in colons of colitis-prone Il10−/− mice transitioned from germ-free to a conventional microbiota. In conclusion, these experiments characterize NFIL3 as an Il12b transcriptional inhibitor. Interactions of macrophages with the enteric microbiota induce NFIL3 to limit their inflammatory capacity. Furthermore, altered intestinal NFIL3 expression may have implications for the pathogenesis of experimental and human inflammatory bowel diseases.

95 citations

Cites background from "The role of the macrophage in senti..."

  • ...Consequently, loss of macrophage tolerance to the enteric microbiota is an important and proximal event in the pathogenesis of the inflammatory bowel diseases (IBDs) (2)....

    [...]

  • ...Innate responses are rapid and directed toward conserved structures on infectious agents recognized by germline-encoded pattern recognition receptors such as TLRs and Nod-like receptors (2)....

    [...]

References
More filters
Journal Article•DOI•
Toll-like receptor signalling

[...]

Shizuo Akira1, Kiyoshi Takeda2•
Osaka University1, Kyushu University2
01 Jul 2004-Nature Reviews Immunology
TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

7,906 citations

Journal Article•DOI•
Exploring the full spectrum of macrophage activation.

[...]

David M. Mosser1, Justin P. Edwards1•
University of Maryland, College Park1
01 Dec 2008-Nature Reviews Immunology
TL;DR: This Review suggests a new grouping of macrophages based on three different homeostatic activities — host defence, wound healing and immune regulation, and proposes that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation.
Abstract: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

7,384 citations

Journal Article•DOI•
Autophagy in the Pathogenesis of Disease

[...]

Beth Levine1, Guido Kroemer2, Guido Kroemer3, Guido Kroemer4•
University of Texas Southwestern Medical Center1, Institut Gustave Roussy2, University of Paris-Sud3, French Institute of Health and Medical Research4
11 Jan 2008-Cell
TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.

6,301 citations

Journal Article•DOI•
Unravelling the pathogenesis of inflammatory bowel disease

[...]

Ramnik J. Xavier1, Daniel K. Podolsky•
Harvard University1
26 Jul 2007-Nature
TL;DR: Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation as mentioned in this paper, which have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis.
Abstract: Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD.

3,831 citations

Journal Article•DOI•
A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism

[...]

Janine L. Coombes1, Karima R.R. Siddiqui1, Carolina V. Arancibia-Cárcamo1, Jason A. Hall2, Cheng-Ming Sun2, Yasmine Belkaid2, Fiona Powrie1 •
University of Oxford1, National Institutes of Health2
06 Aug 2007-Journal of Experimental Medicine
TL;DR: It is shown that after antigen activation in the intestine, naive T cells acquire expression of Foxp3, and RA is identified as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.
Abstract: Foxp3+ regulatory T (T reg) cells play a key role in controlling immune pathological re actions. Many develop their regulatory activity in the thymus, but there is also evidence for development of Foxp3+ T reg cells from naive precursors in the periphery. Recent studies have shown that transforming growth factor (TGF)-β can promote T reg cell development in culture, but little is known about the cellular and molecular mechanisms that mediate this pathway under more physiological conditions. Here, we show that after antigen activation in the intestine, naive T cells acquire expression of Foxp3. Moreover, we identify a population of CD103+ mesenteric lymph node dendritic cells (DCs) that induce the devel opment of Foxp3+ T reg cells. Importantly, promotion of T reg cell responses by CD103+ DCs is dependent on TGF-β and the dietary metabolite, retinoic acid (RA). These results newly identify RA as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.

2,642 citations

Related Papers (5)
Exploring the full spectrum of macrophage activation.

[...]

01 Dec 2008-Nature Reviews Immunology
David M. Mosser, Justin P. Edwards
Unravelling the pathogenesis of inflammatory bowel disease

[...]

26 Jul 2007-Nature
Ramnik J. Xavier, Daniel K. Podolsky
The role of macrophages in inflammatory bowel diseases

[...]

01 Dec 2009-Expert Reviews in Molecular Medicine
Sigrid E.M. Heinsbroek, Siamon Gordon
Macrophages in intestinal homeostasis and inflammation

[...]

01 Jul 2014-Immunological Reviews
Calum C. Bain, Allan McI. Mowat
Functions of Macrophages in the Maintenance of Intestinal Homeostasis

[...]

18 Mar 2019-Clinical & Developmental Immunology
Shuai Wang, Qianhong Ye, Xiangfang Zeng, Shiyan Qiao 
Frequently Asked Questions (1)
Q1. What are the contributions in "The role of the macrophage in sentinel responses in intestinal immunity" ?

Purpose of review—The purpose of this review is to highlight macrophages as central mediators of intestinal immune homeostasis and inflammation. Recent findings—We review recent developments elucidating distinct phenotypic adaptations in intestinal macrophages that determine their functional role in a microbe-rich environment. Converging human genetic and functional findings suggest that dysregulation of macrophage-specific immune responses against an otherwise harmless enteric microbiota are key factors in the pathogenesis of inflammatory bowel disease.