The protective effect of LCN2 knockout on the imiquimod-induced psoriatic mouse model
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PROVIDER: PRJNA1013395 | ENA |
REPOSITORIES: ENA
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Project description:LCN2 demonstrates heightened expression levels in psoriasis, providing insight into its potential implication in the development of this inflammatory cutaneous condition. We here report the discovery that LCN2 is an essential molecule involved in the pathogenesis of psoriasis. Deletion of LCN2 in mice resulted in reduced levels of epidermal hyperplasia and inflammatory infiltration in psoriatic skin lesions, as compared to wild-type mice. Hence, our findings suggest that LCN2 may hold promise as a potential therapeutic target for the treatment of psoriasis.
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Project description:Increased intestinal permeability can exacerbate psoriasis, a systemic inflammatory disease with complex pathogenesis. Using a mouse model of psoriasis elicited by the TLR7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by small-intestinal inflammatory changes associated with eosinophil degranulation which led to impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were accelerated in mice that are prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells treated with media containing eosinophil granule proteins exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal inflammatory changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by eosinophil transfer. Imiquimod levels and eosinophil distribution were positively correlated in the intestine. TLR7-deficient mice did not show intestinal eosinophil degranulation and exhibited attenuated skin and small-intestinal inflammation following imiquimod application. These results suggest a TLR7-dependent bidirectional skin-to-gut communication in psoriatic inflammation, and that intestinal inflammatory changes can accelerate psoriasis.
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Project description:Psoriasis is a chronic inflammatory skin disease of unknown etiology. Although macrophages and dendritic cells (DCs) have been proposed to drive the psoriatic cascade, their largely overlapping phenotype hampered studying their respective role. Topical application of Imiquimod, a Toll-like receptor 7 agonist, induces psoriasis in patients and psoriasiform inflammation in mice. We showed that daily application of Imiquimod for 14 days recapitulated both the initiation and the maintenance phase of psoriasis. Based on our ability to discriminate Langerhans cells (LCs), conventional DCs, monocytes, monocyte-derived DCs and macrophages in the skin, we characterized their dynamics during both phases of psoriasis. During the initiation phase, neutrophils infiltrated the epidermis whereas monocytes and monocyte-derived DCs were predominant in the dermis. During the maintenance phase, LCs and macrophage numbers increased in the epidermis and dermis, respectively. LC expansion resulted from local proliferation, a conclusion supported by transcriptional analysis. Continuous depletion of LCs during the course of Imiquimod treatment aggravated chronic psoriatic symptoms as documented by an increased influx of neutrophils and a stronger inflammation. Therefore, by developing a mouse model that mimics the human disease more accurately, we established that LCs play a negative regulatory role during the maintenance phase of psoriasis.
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Project description:Transcriptional profiling of mouse primary astrocytes comparing control untreated astrocytes with astrocytes treated with recombinant LCN2 protein (10 micro gram/ml). Goal was to determine the effects of LCN2 treatment on global gene expression in astrocytes. A secreted protein lipocalin-2 (LCN2) has been implicated in diverse cellular processes including cell morphology and migration. We have previously demonstrated that lcn2 mediates reactive astrocytosis. In order to further understand the role of lcn2 in the CNS, astrocyte transcriptome was analyzed following LCN2 treatment. Chemokines were the major group of genes upregulated by LCN2. Two-condition experiment, control untreated astrocytes vs. LCN2 protein treated astrocytes. Biological replicates: 1 control replicates, 1 treated replicates.
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2010-06-24 | E-GEOD-20032 | biostudies-arrayexpress
Project description:Transcriptional profiling of mouse primary astrocytes comparing control untreated astrocytes with astrocytes treated with recombinant LCN2 protein (10 micro gram/ml). Goal was to determine the effects of LCN2 treatment on global gene expression in astrocytes. A secreted protein lipocalin-2 (LCN2) has been implicated in diverse cellular processes including cell morphology and migration. We have previously demonstrated that lcn2 mediates reactive astrocytosis. In order to further understand the role of lcn2 in the CNS, astrocyte transcriptome was analyzed following LCN2 treatment. Chemokines were the major group of genes upregulated by LCN2.
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Project description:Background: Distant metastasis remains a major reason for the high recurrence and mortality of colorectal cancer (CRC). However, the underlying molecular mechanisms driving metastasis in CRC remain poorly understood. In this study, we investigated the mechanisms underlying the inhibitory effects of lipocalin-2 (LCN2) on CRC metastasis. Methods: We assessed the expression and clinical significance of LCN2 in human CRC specimens and CRC cell lines using, immunohistochemistry, and western blot analyses. We evaluated the migratory and invasive capabilities of CRC cells influenced by LCN2 using in vitro transwell assays and in vivo lung metastatic models. RNA sequencing and proteome analysis were employed to identify potential downstream targets of LCN2. Rescue experiments were conducted to further elucidate the potential mechanisms of LCN2 and its downstream effectors in CRC. Results: LCN2 exhibited high expression levels in human CRC tissues and an inverse correlation with N classification, advanced AJCC stages, and shorter overall survival. LCN2 expression independently predicted a more favorable outcome for CRC patients. Upregulation of LCN2 effectively suppressed CRC cell metastasis both in vitro and in vivo. Mechanistically, Transforming growth factor beta 1 (TGFB1) and C-X-C motif chemokine ligand 5 (CXCL5) were identified as downstream effectors of LCN2, with LCN2 inhibiting CRC metastasis through repression of the TGFB1/CXCL5 axis. Furthermore, either TGF-βR1 inhibitor SB431542 or CXCR2 antagonist SB225002 treatment moderately decreased the migratory and invasive capabilities of DLD-1-LV-shLCN2 cells, whereas the combination treatment of the two agents dramatically decreased the migratory and invasive capabilities of DLD-1-LV-shLCN2 cells. Conclusions: This study underscores LCN2 as an independent protective factor and prognostic biomarker for CRC patients. Combined treatment with the SB431542 and the SB225002 significantly attenuated LCN2-related CRC metastasis. Targeting the LCN2/TGFB1/CXCL5 axis emerges as a promising therapeutic strategy for managing LCN2-related metastatic CRC.
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Project description:Serotonin and its receptor are known to play a role in regulating immune cells. However, how they affect an autoimmune disease like psoriasis is not well-established and the mechanism remains to be elucidated. Here, we investigated the role played by serotonin 2A receptor (HTR2A) in regulating psoriasis. HTR2A antagonistic drug worsens psoriatic outcome and HTR2A modulation reduced psoriatic inflammation. Using Imiquimod-induced psoriasiform inflammation model, HTR2A-deficient mice experienced exacerbated inflammation. Hematopoietic cells, particularly monocyte-derived Langerhans cells, were responsible for this exacerbated inflammation. Mechanistically, the exacerbated inflammation is due to increased interleukin-23 (IL-23) secretion and HTR2A suppresses it by inhibiting the activation of non-canonical NFkB pathway. Platelet-derived serotonin is the putative agonist modulating HTR2A attenuating psoriatic inflammation. Lastly, our findings in mice were also reproduced clinically. Thus, our data demonstrate platelet serotonin putatively modulates HTR2A attenuating psoriatic inflammation by suppressing IL-23 secretion via inhibiting non-canonical NFkB pathway in monocyte-derived Langerhans cells.
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