Pathogen-Associated Molecules from Gut Translocation Enhance Severity of Cecal Ligation and Puncture Sepsis in Iron-Overload β-Thalassemia Mice
| Autor: | Peerapat Visitchanakun, Saovaros Svasti, Kritsanawan Sae-Khow, Awirut Charoensappakit, Asada Leelahavanichkul, Wilasinee Saisorn, Suthat Fucharoen |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Kidney Lipopolysaccharide Chemistry medicine.medical_treatment Immunology Macrophage polarization Chromosomal translocation Systemic inflammation medicine.disease Sepsis 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Endocrinology medicine.anatomical_structure Cytokine 030220 oncology & carcinogenesis Internal medicine medicine Macrophage cytokine production Immunology and Allergy medicine.symptom |
| Zdroj: | Journal of Inflammation Research. 13:719-735 |
| ISSN: | 1178-7031 |
| DOI: | 10.2147/jir.s273329 |
| Popis: | Introduction Systemic inflammation induced by gut translocation of lipopolysaccharide (LPS), a major component of Gram-negative bacteria, in thalassemia with iron-overload worsens sepsis. However, the impact of (1→3)-β-D-glucan (BG), a major fungal molecule, in iron-overload thalassemia is still unclear. Hence, the influence of BG was explored in 1) iron-overload mice with sepsis induced by cecal ligation and puncture (CLP) surgery; and 2) in bone marrow-derived macrophages (BMMs). Methods The heterozygous β-globin-deficient mice, Hbbth3/+ mice, were used as representative thalassemia (TH) mice. Iron overload was generated by 6 months of oral iron administration before CLP surgery- induced sepsis in TH mice and wild-type (WT) mice. Additionally, BMMs from both mouse strains were used to explore the impact of BG. Results Without sepsis, iron-overload TH mice demonstrated more severe intestinal mucosal injury (gut leakage) with higher LPS and BG in serum, from gut translocation, when compared with WT mice. With CLP in iron-overload mice, sepsis severity in TH mice was more severe than WT as determined by survival analysis, organ injury (kidney and liver), bacteremia, endotoxemia, gut leakage (FITC-dextran) and serum BG. Activation by LPS plus BG (LPS+BG) in BMMs and in peripheral blood-derived neutrophils (both WT and TH cells) demonstrated more prominent cytokine production when compared with LPS activation alone. In parallel, LPS+BG also prominently induced genes expression of M1 macrophage polarization (iNOS, TNF-α and IL-1β) in both WT and TH cells in comparison with LPS activation alone. In addition, LPS+BG activated macrophage cytokine production was enhanced by a high dose of ferric ion (800 mM), more predominantly in TH macrophages compared with WT cells. Moreover, LPS+BG induced higher glycolysis activity with similar respiratory capacity in RAW264.7 (a macrophage cell line) compared with LPS activation alone. These data support an additive pro-inflammatory effect of BG upon LPS. Conclusion The enhanced-severity of sepsis in iron-overload TH mice was due to 1) increased LPS and BG in serum from iron-induced gut-mucosal injury; and 2) the pro-inflammatory amplification by ferric ion on LPS+BG activation. |
| Databáze: | OpenAIRE |
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