Serotonin Regulates Macrophage-Mediated Angiogenesis in a Mouse Model of Colon Cancer Allografts

Nocito, Antonio; Dahm, Felix; Jochum, Wolfram; Jang, Jae Hwi; Georgiev, Panco; Bäder, Michael; Graf, Rolf; Clavien, Pierre‐Alain

doi:10.1158/0008-5472.can-08-0202

Cited by 126 publications

(113 citation statements)

References 26 publications

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“…A link between 5HT and macrophages in cancer progression has been already established, as 5HT enhances angiogenesis in murine colon cancer allografts via the 5HT-dependent reduction of MMP12 expression by tumor-infiltrating macrophages (26). Our results on the phenotypic changes induced by 5HT and BW723C86 on human macrophages are compatible with these findings because: 1) both stimuli inhibit MMP12 mRNA expression (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 89%

“…4). These results are in agreement with the reported ability of 5HT to reduce the expression of MMP12 in murine macrophages (26), and they demonstrate that both 5HT and the 5HT 2B agonist BW723C86 influence the phenotypic macrophage polarization.…”

Section: Ht and 5ht 2b Receptor Engagement Trigger Intracellular Sigsupporting

confidence: 92%

“…Others have shown that 5HT is shuttled from dendritic cells to naive T lymphocytes as a means to modulate T cell activation, proliferation, and differentiation (24), and that it might be necessary for optimal macrophage accessory function (25). In the context of inflammatory pathologies, 5HT regulates macrophagemediated angiogenesis by reducing matrix metalloproteinase 12 (MMP12) expression in tumor-infiltrating macrophages (26), and its contribution to the development of pulmonary arterial hypertension depends on 5HT 2B receptor expression on bone marrow progenitors (27). Thus, 5HT modulates myeloid cell functions in a variable manner, and its effects are dependent on the profile of 5HT receptors expressed by each macrophage subtype.…”

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confidence: 99%

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Serotonin Skews Human Macrophage Polarization through HTR2B and HTR7

Casas-Engel

Domínguez-Soto

Sierra‐Filardi

et al. 2013

The Journal of Immunology

179

126

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Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT1–7) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization–associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT7 mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT2B and 5HT7 receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT2B was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT2B and 5HT7, whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies.

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Section: Discussionsupporting

confidence: 89%

Section: Ht and 5ht 2b Receptor Engagement Trigger Intracellular Sigsupporting

confidence: 92%

mentioning

confidence: 99%

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Serotonin Skews Human Macrophage Polarization through HTR2B and HTR7

Casas-Engel

Domínguez-Soto

Sierra‐Filardi

et al. 2013

The Journal of Immunology

179

126

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“…In addition to enhancing our understanding of the role of 5-HT on immune cell signaling and pathogenesis of colitis, this study identified a potential therapeutic strategy for intestinal inflammatory disorders, including IBD, by targeting 5-HT signaling. Intestinal 5-HT has not only been shown to be important in modulating gut inflammation, but recent studies have also shown that 5-HT deficiency causes slower growth of colon cancer allografts in vivo (73), and reduction in gut-derived 5-HT synthesis decreases development of osteoporosis by promoting bone formation (74). Thus, in a wider perspective, these data have implications not only in developing strategies in ameliorating GI inflammatory disorders such as IBD, but also in non-GI inflammatory conditions that are associated with alterations in 5-HT signaling in the gut.…”

Section: Cd11cmentioning

confidence: 99%

Targeted Inhibition of Serotonin Type 7 (5-HT7) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation

Kim

Bridle

Ghia

et al. 2013

The Journal of Immunology

109

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Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7−/−) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7−/− mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7−/− mice and in mice reconstituted with bone marrow cells from 5-HT7−/− mice compared with control mice after DSS colitis. 5-HT7−/− mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

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“…Serotonin does not enhance tumor cell proliferation, but acts as a regulator of angiogenesis by reducing the expression of matrix metalloproteinase 12 (MMP-12) in tumor-infiltrating macrophages, entailing lower levels of angiostatin-an endogenous inhibitor of angiogenesis. Accordingly, serotonin deficiency causes slower growth of colon tumors by reducing vascularity, thus increasing hypoxia and spontaneous necrosis [35]. In alveolar macrophages serotonin significantly inhibits the production of tumor necrosis factor (TNF) and interleukin (IL)-12, whereas IL-10, NO and PGE(2) production are increased.…”

Section: Serotoninmentioning

confidence: 99%

Some Aspects of the Normal Role of Neuromodulators in the Immune System

Smythies¹

2011

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Serotonin Regulates Macrophage-Mediated Angiogenesis in a Mouse Model of Colon Cancer Allografts

Cited by 126 publications

References 26 publications

Serotonin Skews Human Macrophage Polarization through HTR2B and HTR7

Serotonin Skews Human Macrophage Polarization through HTR2B and HTR7

Targeted Inhibition of Serotonin Type 7 (5-HT7) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation

Some Aspects of the Normal Role of Neuromodulators in the Immune System

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