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- de Jong, S, et al.
(författare)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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- Li, MY, et al.
(författare)
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Ncf1 Governs Immune Niches in the Lung to Mediate Pulmonary Inflammation in Mice
- 2021
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 783944-
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil cytosolic factor 1 (Ncf1) is a major genetic factor associated with autoimmune diseases and has been identified as a key player in autoimmune mediated inflammation. We addressed the role ofNcf1in an antigen-induced pulmonary inflammation model, and found that theNcf1m1jmutation, causing a deficient reactive oxygen species response, alleviated disease. TheNcf1m1jmutation was associated with a reduced inflammatory cell infiltration in airways, but had limited effect on mucus secretion, antibody production and lung fibrosis. The disease remission in theNcf1mutated mice was reversed when functionalNcf1was transgenically expressed in alveolar macrophages, suggesting that the cellular inflammation was depended on functionalNcf1in alveolar macrophages. By determining cytokine and chemokine profiles in lung and serum, we found thatNcf1deficiency allowed an increased expression of Th1 cytokines, including TNF-α, IFN-γ and IL-12. Since also epithelial cytokines were found to be regulated byNcf1, we tested the effect ofNcf1in IL-33 and IL-25 induced lung inflammation models. Mice with theNcf1m1jmutation showed less sensitivity to IL-33, but not IL-25, induced lung inflammation, in a macrophage independent manner. The mice with deficientNcf1showed a reduced eosinophil infiltration and group 2 innate lymphoid cell (ILC2) activation. The production of IFN-γ in CD4+T cells was increased, whereas IL-5 and IL-13 in ILC2 were decreased. Importantly, anti-IFN-γ antibody treatment ofNcf1deficient mice increased eosinophil infiltration and rescued ILC2 activation in the lung. We conclude thatNcf1deficiency enhances Th1 response, deactivates ILC2, and protects against pulmonitis.
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- Peng, YZ, et al.
(författare)
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SLC38A6 expression in macrophages exacerbates pulmonary inflammation
- 2023
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Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X. ; 24:1, s. 33-
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary inflammation involves complex changes of the immune cells, in which macrophages play important roles and their function might be influenced by metabolism. Slc38a6 acts as a carrier of nutrient for macrophages (Mφ) to exert the function. In this study, pneumonia patient blood was found up-regulated SLC38A6 expression, which correlated with monocytes number and white blood cell number. The similar result was also shown in LPS induced sepsis mice. To reveal the key role of Slc38a6, we used systemic and conditional knock-out mice. Either systemic or LyzCRE specific knock-out could alleviate the severity of sepsis mice, reduce the proinflammatory cytokine TNF-α and IL-1β expression in serum and decrease the monocytes number in bronchial alveolar lavage and peritoneal lavage via flow cytometry. In order to reveal the signal of up-regulated Slc38a6, the Tlr4 signal inhibitor TAK242 and TLR4 knock-out mice were used. By blocking Tlr4 signal in macrophages via TAK242, the expression of Slc38a6 was down-regulated synchronously, and the same results were also found in Tlr4 knock-out macrophages. However, in the overexpressed Slc38a6 macrophages, blocking Tlr4 signal via TAK242, 20% of the mRNA expression of IL-1β still could be expressed, indicating that up-regulated Slc38a6 participates in IL-1β expression process. Collectively, it is the first time showed that an amino acid transporter SLC38A6 up-regulated in monocytes/macrophages promotes activation in pulmonary inflammation. SLC38A6 might be a promising target molecule for pulmonary inflammation treatment.
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