RESUMO
Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for preventing and treating CRC. Fibrinogen C domain-containing 1 (FIBCD1), a chitin-binding transmembrane protein predominantly found on human intestinal epithelial cells (IECs), has garnered attention in previous research for its ability to effectively suppress inflammatory responses and promote tissue homeostasis at mucosal barriers. Methods: In this study, we investigated the role of FIBCD1 in CRC development using transgenic mice that mimic human expression of FIBCD1 at the intestinal mucosal barrier. To model aspects of CRC, we employed the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. Additionally, we examined the expression pattern of FIBCD1 in surgical specimens obtained from human CRC patients by immunohistochemical methods. By accessing public data repositories, we further evaluated FIBCD1 expression in colon adenocarcinoma and explored survival outcomes associated with FIBCD1 expression. Results: Here, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis in mice. Furthermore, we identify a soluble variant of FIBCD1 that is significantly increased in feces during acute inflammation. Finally, we demonstrate increased expression of FIBCD1 by immunohistochemistry in human CRC specimens at more developed tumor stages. These results are further supported by bioinformatic analyses of publicly available repositories, indicating increased FIBCD1 expression in tumor tissues, where higher expression is associated with unfavorable prognosis. Conclusion: Collectively, these findings suggest that FIBCD1 influences early inflammatory responses in the AOM/DSS model, leading to a reduction in tumor size and burden. The increased expression of FIBCD1 in human CRC samples raises intriguing questions regarding its role in CRC, positioning it as a compelling candidate and novel molecular target for future research.
RESUMO
PURPOSE: Chemotherapy-induced gastrointestinal toxicity is a common adverse event during chemotherapeutic treatment. No uniformly applicable strategies exist to predict, prevent, or treat gastrointestinal toxicity. Thus, a goal of mucositis research is to identify targets for therapeutic interventions and individualized risk prediction. Fibrinogen C domain containing 1 (FIBCD1) is a transmembrane protein expressed in human intestinal epithelial cells with functions in the innate immune system. Previous observations have shown that FIBCD1 ameliorates dextran sulfate sodium (DSS)-induced intestinal inflammation in vivo. We evaluated the effect of FIBCD1 in a murine model of chemotherapy-induced gastrointestinal toxicity and inflammation. METHODS: Transgenic (Tg) mice overexpressing FIBCD1 in the intestinal epithelium (Fibcd1Tg) and wild-type (WT) littermates (C57BL/6N) were randomized to receive an intraperitoneal injection of doxorubicin 20 mg/kg or saline and were terminated 2 or 7 days after the injection. Gastrointestinal toxicity was evaluated by weight change, intestinal length, villus height/crypt depth, and histological mucositis score. Expression of inflammatory markers (IL-6, IL-1ß, and Tnfα) was measured by quantitative real-time PCR in intestinal tissue samples. RESULTS: Following doxorubicin treatment, WT mice exhibited an increased weight loss compared with Tg littermates (p < 0.001). No differences between genotypes were seen in mucositis score, intestinal length, villus height/crypt depth, or IL-6, IL-1ß, and Tnfα expression. CONCLUSION: Our findings suggest that FIBCD1 could ameliorate chemotherapy-induced gastrointestinal toxicity by reducing weight loss; however, the mechanism of this possible protective effect remains to be defined warranting additional investigations.
Assuntos
Antineoplásicos/uso terapêutico , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Receptores de Superfície Celular/uso terapêutico , Redução de Peso/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Genótipo , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the importance and regulation of these changes remain unclear. We found that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified conventional dendritic cells (cDCs) as a source of hepcidin that is induced by microbial stimulation in mice, prominent in the inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and consequently facilitated intestinal repair. Collectively, these results identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity.
Assuntos
Células Dendríticas/metabolismo , Microbioma Gastrointestinal , Hepcidinas/metabolismo , Enteropatias/microbiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiologia , Ferro/metabolismo , Animais , Proteínas de Transporte de Cátions/metabolismo , Transplante de Microbiota Fecal , Deleção de Genes , Hepcidinas/genética , Homeostase , Camundongos , Camundongos Mutantes , Fagócitos/metabolismoAssuntos
Aspergilose/imunologia , Aspergilose/microbiologia , Aspergillus fumigatus/fisiologia , Polissacarídeos Fúngicos/imunologia , Lectinas/imunologia , Pulmão/imunologia , Aspergilose/genética , Aspergillus fumigatus/genética , Aspergillus fumigatus/imunologia , Ativação do Complemento , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Lectinas/genética , Pulmão/microbiologia , Ligação Proteica , beta-Glucanas/metabolismo , FicolinasRESUMO
CD163-L1 belongs to the group B scavenger receptor cysteine-rich family of proteins, where the CD163-L1 gene arose by duplication of the gene encoding the hemoglobin scavenger receptor CD163 in late evolution. The current data demonstrate that CD163-L1 is highly expressed and colocalizes with CD163 on large subsets of macrophages, but in contrast to CD163 the expression is low or absent in monocytes and in alveolar macrophages, glia, and Kupffer cells. The expression of CD163-L1 increases when cultured monocytes are M-CSF stimulated to macrophages, and the expression is further increased by the acute-phase mediator IL-6 and the anti-inflammatory mediator IL-10 but is suppressed by the proinflammatory mediators IL-4, IL-13, TNF-α, and LPS/IFN-γ. Furthermore, we show that CD163-L1 is an endocytic receptor, which internalizes independently of cross-linking through a clathrin-mediated pathway. Two cytoplasmic splice variants of CD163-L1 are differentially expressed and have different subcellular distribution patterns. Despite its many similarities to CD163, CD163-L1 does not possess measurable affinity for CD163 ligands such as the haptoglobin-hemoglobin complex or various bacteria. In conclusion, CD163-L1 exhibits similarity to CD163 in terms of structure and regulated expression in cultured monocytes but shows clear differences compared with the known CD163 ligand preferences and expression pattern in the pool of tissue macrophages. We postulate that CD163-L1 functions as a scavenger receptor for one or several ligands that might have a role in resolution of inflammation.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Endocitose/imunologia , Mediadores da Inflamação/fisiologia , Macrófagos/imunologia , Macrófagos/patologia , Receptores de Superfície Celular/metabolismo , Animais , Antígenos CD/biossíntese , Antígenos CD/fisiologia , Antígenos de Diferenciação Mielomonocítica/biossíntese , Antígenos de Diferenciação Mielomonocítica/fisiologia , Diferenciação Celular/imunologia , Células Cultivadas , Células HEK293 , Células HL-60 , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Células Jurkat , Células de Kupffer/imunologia , Células de Kupffer/patologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Macrófagos/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Neuroglia/imunologia , Neuroglia/patologia , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/fisiologia , Células U937RESUMO
Liposomal nucleic acid delivery is a preferred option for therapeutic settings. The cellular pattern recognition molecule DMBT1, secreted at high levels in various diseases, and synthetic mimics efficiently inhibit liposomal nucleic acid delivery to human cells. These findings may have relevance for therapeutic nucleic acid delivery strategies.