The Role of Macrophages and Dendritic Cells in the Initiation of Inflammation in IBD

Steinbach, Erin C.; Plevy, Scott E.

doi:10.1097/mib.0b013e3182a69dca

Cited by 208 publications

(178 citation statements)

References 150 publications

(170 reference statements)

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“…Macrophages are the most abundant leukocytes in the healthy intestinal LP and contribute significantly to gut homeostasis (22,29) through several mechanisms including phagocytosis, degradation of microorganisms and dead tissue cells, and epithelial cell restitution (22). Importantly, they produce large amounts of IL-10, which blocks Toll-like receptor (TLR)-induced inflammatory responses and enhances the survival and function of local FOXP3…”

Section: Discussionmentioning

confidence: 99%

“…Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGF␤RII expression in macrophages and the acquisition of a "regulatory" phenotype that contributes to intestinal mucosal homeostasis. colitis; colonic macrophages; epigenetics; histone acetyl transferase; Krüppel-like factor MACROPHAGES ARE the most abundant mononuclear phagocytes in the healthy intestinal lamina propria (LP) and are important regulators of immune responses during intestinal inflammation (26,29,42). In the murine system, intestinal macrophages rely on constant replenishment by Ly6C ϩ blood monocytes conditioned to acquire a noninflammatory profile and differentiate into chemokine receptor CX3CR1 hi "regulatory" macrophages (1,2,20,33,42).…”

Section: And Cd4mentioning

confidence: 99%

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Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation

Papadakis

Krempski

Svingen

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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ϩ T lymphocytes. In the present study, we demonstrate a novel role for KLF10 in the regulation of TGF␤RII expression with functional relevance in macrophage differentiation and activation. We first show that transfer of KLF10 Ϫ/Ϫ bone marrow-derived macrophages into wild-type (WT) mice leads to exacerbation of experimental colitis. At the cell biological level, using two phenotypic strategies, we show that KLF10-deficient mice have an altered colonic macrophage phenotype with higher frequency of proinflammatory LyC6 ϩ MHCII ϩ cells and a reciprocal decrease of the anti-inflammatory LyC6Ϫ MHCII ϩ subset. Additionally, the anti-inflammatory CD11b ϩ CX3CR1 hi subset of colonic macrophages is significantly decreased in KLF10 Ϫ/Ϫ compared with WT mice under inflammatory conditions. Molecularly, CD11b ϩ colonic macrophages from KLF10 Ϫ/Ϫ mice exhibit a proinflammatory cytokine profile with increased production of TNF-␣ and lower production of IL-10 in response to LPS stimulation. Because KLF10 is a transcription factor, we explored how this protein may regulate macrophage function. Consequently, we analyzed the expression of TGF␤RII expression in colonic macrophages and found that, in the absence of KLF10, macrophages express lower levels of TGF␤RII and display an attenuated Smad-2 phosphorylation following TGF-␤ 1 stimulation. We further show that KLF10 directly binds to the TGF␤RII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGF␤RII expression in macrophages and the acquisition of a "regulatory" phenotype that contributes to intestinal mucosal homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: And Cd4mentioning

confidence: 99%

Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation

Papadakis

Krempski

Svingen

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Macrophages are a key component of host innate immune defense in the intestines, limiting systemic microbial dissemination by destroying potential invaders through phagocytosis, while also sensing and responding to microbial stimuli and informing consequent host immune responses (22). Through pattern recognition receptors (PRRs), macrophages recognize the conserved microbial molecular patterns synthesized by resident and pathogenic intestinal bacteria, including extracellular structures, such as fimbriae, flagella, lipopolysaccharides, and peptidoglycan.…”

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confidence: 99%

Adherent-Invasive Escherichia coli Production of Cellulose Influences Iron-Induced Bacterial Aggregation, Phagocytosis, and Induction of Colitis

et al. 2015

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Adherent-invasive Escherichia coli (AIEC), a functionally distinct subset of resident intestinal E. coli associated with Crohn's disease, is characterized by enhanced epithelial adhesion and invasion, survival within macrophages, and biofilm formation. Environmental factors, such as iron, modulate E. coli production of extracellular structures, which in turn influence the formation of multicellular communities, such as biofilms, and bacterial interactions with host cells. However, the physiological and functional responses of AIEC to variable iron availability have not been thoroughly investigated. We therefore characterized the impact of iron on the physiology of AIEC strain NC101 and subsequent interactions with macrophages. Iron promoted the cellulose-dependent aggregation of NC101. Bacterial cells recovered from the aggregates were more susceptible to phagocytosis than planktonic cells, which corresponded with the decreased macrophage production of the proinflammatory cytokine interleukin-12 (IL-12) p40. Prevention of aggregate formation through the disruption of cellulose production reduced the phagocytosis of iron-exposed NC101. In contrast, under iron-limiting conditions, where NC101 aggregation is not induced, the disruption of cellulose production enhanced NC101 phagocytosis and decreased macrophage secretion of IL-12 p40. Finally, abrogation of cellulose production reduced NC101 induction of colitis when NC101 was monoassociated in inflammation-prone Il10 ؊/؊ mice. Taken together, our results introduce cellulose as a novel physiological factor that impacts host-microbe-environment interactions and alters the proinflammatory potential of AIEC.

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“…Differentiation of macrophages from monocytes in the intestinal mucosa is accompanied by the acquisition of a typical functional phenotype [4,5,12,13]. The differentiation of monocytes into macrophages normally occurs under ‘non-inflammatory' conditions.…”

Section: Tissue-specific Differentiation Of Innate Immune Cellsmentioning

confidence: 99%

“…Cells of the innate immune system have been shown to play an important role during the initiation and chronification of IBD [4,5,6]. IBD has become a prototype of an immune disease partially caused by a high number of genetic risk variation, e.g.…”

Section: Introductionmentioning

confidence: 99%

The Innate Immune System: A Trigger for Many Chronic Inflammatory Intestinal Diseases

Kamada

Rogler

2016

Inflamm Intest Dis

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Background: Mononuclear phagocytes, such as monocytes, macrophages, and dendritic cells, are important cellular components of the innate immune system that contribute to the pathogenesis of many intestinal inflammatory diseases. Summary: While mononuclear phagocytes play a key role in the induction of inflammation in many different tissues through production of pro-inflammatory cytokines and chemokines (such as IL-1, TNF, IL-6, IL-8 and MCP-1), free oxygen radicals (also termed ‘oxidative burst'), proteases (such as cathepsins) and tissue-degrading enzymes (such as metalloproteinases), resident macrophages as well as dendritic cells in the intestine display an anergic and ‘tolerogenic' phenotype mediating tolerance to commensal bacteria. In recent years many single nucleotide polymorphisms (SNPs) in genes mainly expressed in the above-mentioned cell types have been identified to convey an increased risk of autoimmune diseases. SNPs in the NOD2, ATG16L1 and TNFSF15 genes, which are involved in the function of the innate immune cells, are identified as risk factors for Crohn's disease (CD). Of note, these genes are involved in the different functions in the innate immune cells. For example, while NOD2 is required for intracellular recognition of microbial components, ATG16L1 is involved in autophagy responses against intracellular microbes. Likewise, TNFSF15 contributes to the induction of inflammatory responses by innate immune cells. Furthermore, the frequency of mutations in these genes differs by ethnicity. Genetic variations in the NOD2 and ATG16L1 genes are associated with CD in Caucasians but much less in Eastern Asian populations, whereas SNPs in TNFSF15 are dominated in Asian populations. Thus, different genetic risks may eventually lead to similar impairments in innate immune cells, thereby developing the same disease in Western and Asian patients with CD. Key Messages: Despite differences in risk genes, similar mechanisms associated with the innate immune system may trigger autoimmune and chronic inflammatory intestinal diseases in East and West.

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The Role of Macrophages and Dendritic Cells in the Initiation of Inflammation in IBD

Cited by 208 publications

References 150 publications

Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation

Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation

Adherent-Invasive Escherichia coli Production of Cellulose Influences Iron-Induced Bacterial Aggregation, Phagocytosis, and Induction of Colitis

The Innate Immune System: A Trigger for Many Chronic Inflammatory Intestinal Diseases

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