Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles

Kayama, Hisako; Kohyama, Masanori; Okuzaki, Daisuke; Motooka, Daisuke; Barman, Soumik; Okumura, Ryu; Muneta, Masato; Hoshino, Katsuaki; Sasaki, Izumi; Ise, Wataru; Matsuo, Hiroshi; Nishimura, Junichi; Kurosaki, Tomohiro; Nakamura, Shota; Arase, Hisashi; Kaisho, Tsuneyasu; Takeda, Kiyoshi

doi:10.1073/pnas.1808426115

Cited by 35 publications

(39 citation statements)

References 43 publications

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“…However, the level of TNFα in the colon was unchanged in orange pectin-fed mice (Figure 7I). Knowing that intestinal macrophages have been reported to supply IL-6 and raise the inflammatory response in DSS-induced colitis (46), these results indicated that orange pectin regulates IL-6 production in colon, thereby attenuating the inflammatory response.…”

Section: Orange Pectin Not Citrus Pectin Ameliorates Dss-induced Comentioning

confidence: 72%

“…A recent report showed that intestinal macrophage subsets are involved in the initiation of murine colitis (34). Furthermore, Kayama et al reported that CX3CR1 + intestinal macrophages were able to produce high concentrations of IL-1β and IL-6 via activation of TLR4, and that suppression of this pathway resulted in the amelioration of DSS-induced colitis (46). Our present results showed that colonic IL-6 levels were decreased in orange pectin-fed mice both in TNBS-and DSSinduced colitis (Figures 5E, 7H).…”

Section: Discussionmentioning

confidence: 99%

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Dietary Fiber Pectin Ameliorates Experimental Colitis in a Neutral Sugar Side Chain-Dependent Manner

et al. 2019

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Dietary fiber, with intake of soluble fibers in particular, has been reported to lower the risk for developing inflammatory bowel diseases (IBD). This is at least partly attributable to the fermentation of dietary fiber by the colonic microbiota to produce short chain fatty acids. Pectin, a widely consumed soluble fiber, is known to exert a protective effect in murine models of IBD, but the underlying mechanism remains elusive. Apart from having a prebiotic effect, it has been suggested that pectin direct influences host cells by modulating the inflammatory response in a manner dependent on its neutral sugar side chains. Here we examined the effect of the side chain content of pectin on the pathogenesis of experimental colitis in mice. Male C57BL/6 mice were fed a pectin-free diet, or a diet supplemented with characteristically high (5% orange pectin) or low (5% citrus pectin) side chain content for 10-14 days, and then administered 2,4,6-trinitrobenzene sulfonic acid or dextran sulfate sodium to induce colitis. We found that the clinical symptoms and tissue damage in the colon were ameliorated in mice that were pre-fed with orange pectin, but not in those pre-fed with citrus pectin. Although the population of CD4 + Foxp + regulatory T cells and CD4 + RORγt + inflammatory T cells in the colon were comparable between citrus and orange pectin-fed mice, colonic interleukin (IL)-1β and IL-6 levels in orange pectin-fed mice were significantly decreased. The fecal concentration of propionic acid in orange pectin-fed mice was slightly but significantly higher than that in control and citrus pectin-fed mice but the cecal concentration of propionic acid after the induction of TNBS colitis was comparable between orange and citrus pectin-fed mice. Furthermore, the protective effect of orange pectin against colitis was observed even in mice treated with antibiotics. IL-6 production from RAW264.7 cells stimulated with the toll-like receptor agonist Pam3CSK4 or lipopolysaccharide was suppressed by pre-treatment with orange pectin in vitro. Taken together, these results suggest that the side chains of pectin not only augment prebiotic effects but also directly regulate IL-6 production from intestinal host cells in a microbiota-independent fashion to attenuate colitis.

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Section: Orange Pectin Not Citrus Pectin Ameliorates Dss-induced Comentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Dietary Fiber Pectin Ameliorates Experimental Colitis in a Neutral Sugar Side Chain-Dependent Manner

et al. 2019

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“…Administration of heme and subsequent induction of HO-1 in peritoneal macrophages alleviated inflammation in a choline-deficient diet mouse model of pancreatitis [91]. Similarly, peritoneal administration of heme was found to protect against experimental colitis via up-regulation of Spi-C in macrophages [92]. The anti-inflammatory effects of Spi-C are mediated by its association with the interferon regulatory factor (IRF)5, thereby blocking the interaction of IRF5 with the NF-kB subunit p65, which is required for the transcriptional regulation of pro-inflammatory genes such as IL-6 and IL-1α.…”

Section: Heme As An Anti-inflammatory Signal In Macrophagesmentioning

confidence: 93%

“…The anti-inflammatory effects of Spi-C are mediated by its association with the interferon regulatory factor (IRF)5, thereby blocking the interaction of IRF5 with the NF-kB subunit p65, which is required for the transcriptional regulation of pro-inflammatory genes such as IL-6 and IL-1α. Similar to RPMs, intestinal macrophages also exhibit high basal levels of Spi-C suggesting that heme might also be a functional demand signal required for the intestinal macrophage phenotype in physiological conditions [92]. This might further contribute to the non-inflammatory status of these cells which may allow their co-existence with the gut microbiome.…”

Section: Heme As An Anti-inflammatory Signal In Macrophagesmentioning

confidence: 99%

Interplay of Heme with Macrophages in Homeostasis and Inflammation

Pradhan

Vijayan

Gueler

et al. 2020

IJMS

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Macrophages are an integral part of the mononuclear phagocyte system that is critical for maintaining immune homeostasis. They play a key role for initiation and modulation of immunological responses in inflammation and infection. Moreover, macrophages exhibit a wide spectrum of tissue-specific phenotypes in steady-state and pathophysiological conditions. Recent clinical and experimental evidence indicates that the ubiquitous compound heme is a crucial regulator of these cells, e.g., in the differentiation of monocytes to tissue-resident macrophages and/ or in activation by inflammatory stimuli. Notably, heme, an iron containing tetrapyrrole, is essential as a prosthetic group of hemoproteins (e.g., hemoglobin and cytochromes), whereas non-protein bound free or labile heme can be harmful via pro-oxidant, pro-inflammatory, and cytotoxic effects. In this review, it will be discussed how the complex interplay of heme with macrophages regulates homeostasis and inflammation via modulating macrophage inflammatory characteristics and/ or hematopoiesis. A particular focus will be the distinct roles of intra- and extracellular labile heme and the regulation of its availability by heme-binding proteins. Finally, it will be addressed how heme modulates macrophage functions via specific transcriptional factors, in particular the nuclear repressor BTB and CNC homologue (BACH)1 and Spi-C.

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“…98 Interestingly, hemoglobin released from hemorrhaging tissue in experimental colitis limits pro-inflammatory gene expression in Cx3cr1 high macrophages, thus limiting intestinal inflammation in DSS-induced colitis. 99 As in the healthy gut, however, resident macrophages may contribute to the recruitment of monocytes through release of CCR2 ligands. This has been demonstrated in the case of the specialized niche of CD169 + macrophages located preferentially around the base of intestinal crypts, adjacent to blood vessels and lymphatics, that have been shown to produce CCL8 in response to inflammation or injury to attract inflammatory Ly6C high monocytes ( Figure 3B).…”

Section: Lamina Propria Macrophages In Intestinal Inflammation and mentioning

confidence: 99%

Intestinal resident macrophages: Multitaskers of the gut

Viola

Boeckxstaens

2020

Neurogastroenterology Motil

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Background Intestinal resident macrophages play a crucial role in homeostasis and have been implicated in numerous gastrointestinal diseases. While historically believed to be largely of hematopoietic origin, recent advances in fate‐mapping technology have unveiled the existence of long‐lived, self‐maintaining populations located in specific niches throughout the gut wall. Furthermore, the advent of single‐cell technology has enabled an unprecedented characterization of the functional specialization of tissue‐resident macrophages throughout the gastrointestinal tract. Purpose The purpose of this review was to provide a panorama on intestinal resident macrophages, with particular focus to the recent advances in the field. Here, we discuss the functions and phenotype of intestinal resident macrophages and, where possible, the functional specialization of these cells in response to the niche they occupy. Furthermore, we will discuss their role in gastrointestinal diseases.

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Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles

Cited by 35 publications

References 43 publications

Dietary Fiber Pectin Ameliorates Experimental Colitis in a Neutral Sugar Side Chain-Dependent Manner

Dietary Fiber Pectin Ameliorates Experimental Colitis in a Neutral Sugar Side Chain-Dependent Manner

Interplay of Heme with Macrophages in Homeostasis and Inflammation

Intestinal resident macrophages: Multitaskers of the gut

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