The pathogen receptor liver and lymph node sinusoidal endotelial cell C-type lectin is expressed in human Kupffer cells and regulated by PU.1

Self Cite

179

126

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.

Section: Methodsmentioning

confidence: 99%

Serotonin Skews Human Macrophage Polarization through HTR2B and HTR7

Casas-Engel

Domínguez-Soto

Sierra‐Filardi

et al. 2013

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“…Transfection in F9 cells was performed with Superfect (Qiagen, Hilden, Germany) according to the manufacturer's instructions. THP-1 cells were transfected using DEAE-dextran as previously described (37,38). The DC-SIGN-based reporter gene constructs pCD209-1600 and pCD209-468 reporter plasmids have been previously described (37).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…P3X63Ag8 (X63) myeloma supernatants and FITC-labeled isotype-matched irrelevant Abs were included as negative controls. Immunostaining was performed on formalin-fixed, paraffin-embedded sections from tumor tissues as previously described (38). Anti-CD68 (clone PG-M1; DakoCytomation) mAb (1/100 dilution) and a polyclonal antiserum against human DC-SIGN (DSG-1; 1/1000 dilution) were used as primary Abs.…”

Section: Flow Cytometry Immunohistochemistry and Absmentioning

confidence: 99%

Dendritic Cell-Specific ICAM-3–Grabbing Nonintegrin Expression on M2-Polarized and Tumor-Associated Macrophages Is Macrophage-CSF Dependent and Enhanced by Tumor-Derived IL-6 and IL-10

Domínguez-Soto

Sierra‐Filardi

Puig‐Kröger

et al. 2011

Self Cite

123

117

Dendritic cell-specific ICAM-3–grabbing nonintegrin (DC-SIGN; CD209) is a human pathogen-attachment C-type lectin with no obvious murine ortholog and for which ligation leads to enhanced anti-inflammatory cytokine release and altered proinflammatory cytokine production. Although induced by IL-4 in monocytes and considered as a DC marker, DC-SIGN expression on human APCs under homeostatic conditions is so far unexplained. We report in this study that M-CSF enhances DC-SIGN expression on in vitro derived anti-inflammatory macrophages and that M-CSF mediates the induction of DC-SIGN by fibroblast- and tumor cell-conditioned media. The M-CSF–inducible DC-SIGN expression along monocyte-to-macrophage differentiation is dependent on JNK and STAT3 activation, potentiated by STAT3-activating cytokines (IL-6, IL-10), and abrogated by the M1-polarizing cytokine GM-CSF. In pathological settings, DC-SIGN expression is detected in tumor tissues and on ex vivo-isolated CD14+ CD163+ IL-10–producing tumor-associated macrophages. Importantly, DC-SIGN Abs reduced the release of IL-10 from macrophages exposed to Lewisx-expressing SKBR3 tumor cells. These results indicate that DC-SIGN is expressed on both wound-healing (IL-4–dependent) and regulatory (M-CSF–dependent) alternative (M2) macrophages and that DC-SIGN expression on tumor-associated macrophages might help tumor progression by contributing to the maintenance of an immunosuppressive environment.

“…Liver sinusoidal endothelial cell lectin (LSECtin), which is a cell-surface molecule that belongs to the C-type lectin receptor family, is constitutively and specifically expressed in LSECs and Kupffer cells (8)(9)(10). We recently reported that LSECtin suppresses intrahepatic T cell immunity and limits immune-mediated liver injury during Con A-induced experimental acute hepatitis (10).…”

mentioning

confidence: 99%

Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

Liu

Wang

et al. 2013

Liver sinusoidal endothelial cell lectin (LSECtin) was recently reported to suppress intrahepatic T cell immunity and to limit immune-mediated liver injury. However, its role in the outcome and pathogenesis of viral infection has not yet been elucidated. Using a mouse model infected with a hepatotropic adenovirus, we found that the absence of LSECtin led to a higher frequency of intrahepatic effector CTLs. These cells produced higher levels of antiviral cytokines and cytotoxic factors and exhibited an increased expression of the transcription factors T-bet and Runx3. This phenotype observed in the LSECtin-knockout cells mediated a more efficient virus-specific cytotoxity compared with that of wild-type cells. As a consequence, LSECtin deficiency significantly accelerated liver adenovirus clearance. In contrast, LSECtin upregulation in the liver delayed viral clearance; this delayed clearance was accompanied by the downregulation of the antiviral activity of CTLs. We further constructed an immunocompetent mouse model of acute hepatitis B viral infection to demonstrate that LSECtin significantly delayed the clearance of hepatitis B virus from blood and infected hepatocytes by limiting the frequency of hepatitis B virus–specific IFN-γ–producing cells. Consistent with this function, LSECtin was upregulated in the liver of mouse models of viral hepatitis. Taken together, our results suggest that LSECtin may facilitate the reduction of liver inflammation at the cost of delaying virus clearance and that this effect might be hijacked by the virus as an escape mechanism.