Deletion of the Mitochondrial Membrane Protein Fam210b Is Associated with the Development of Systemic Lupus Erythematosus.

Mitochondrial dysfunction has been increasingly recognized as a trigger for systemic lupus erythematosus (SLE). Recent bioinformatics studies have suggested Fam210b as a significant candidate for the classification and therapeutic targeting of SLE. To experimentally prove the role of Fam210b in SLE, we constructed Fam210b knockout (Fam210b-/-) mice using the CRISPR-Cas9 method. We found that approximately 15.68% of Fam210b-/- mice spontaneously developed lupus-like autoimmunity, which was characterized by skin ulcerations, splenomegaly, and an increase in anti-double-stranded DNA (anti-dsDNA) IgG antibodies and anti-nuclear antibodies(ANA). Single-cell sequencing showed that Fam210b was mainly expressed in erythroid cells. Critically, the knockout of Fam210b resulted in abnormal erythrocyte differentiation and development in the spleens of mice. Concurrently, the spleens exhibited an increased number of CD71+ erythroid cells, along with elevated levels of reactive oxygen species (ROS) in the erythrocytes. The co-culture of CD71+ erythroid cells and lymphocytes resulted in lymphocyte activation and promoted dsDNA and IgG production. In summary, Fam210b knockout leads to a low probability of lupus-like symptoms in mice through the overproduction of ROS in CD71+ erythroid cells. Thus, Fam210b reduction may serve as a novel key marker that triggers the development of SLE.

Mendelian randomization study on the causal effect of herpes simplex virus infection on idiopathic pulmonary fibrosis.

BACKGROUND: Previous observational studies have shown that past infection of herpes simplex virus (HSV) is associated with idiopathic pulmonary fibrosis (IPF). The present study aims to identify the causal link between HSV infection (exposure factor) and IPF (outcome factor). RESEARCH DESIGN AND METHODS: To date, the largest publicly available genome-wide association study (GWAS) for HSV infection (1,595 cases and 211,856 controls from Finnish ancestry) and for IPF (1,028 cases and 196,986 controls from Finnish ancestry) were used to perform this two-sample Mendelian randomization (MR) study. RESULTS: We found no significant pleiotropy or heterogeneity of all selected nine HSV infection-associated genetic instrumental variants (IVs) in IPF GWAS dataset. Interestingly, we found that as HSV infection genetically increased, IPF risk increased based on an inverse-variance weighted (IVW) analysis (odds ratio [OR] = 1.280, 95% confidence interval [CI]: 1.048-1.563; p = 0.015) and weighted median (OR = 1.321, 95% CI: 1.032-1.692; p = 0.027). CONCLUSIONS: Our analysis suggests a causal effect of genetically increased HSV infection on IPF risk. Thus, HSV infection may be a potential risk factor for IPF.

Human C15orf39 Inhibits Inflammatory Response via PRMT2 in Human Microglial HMC3 Cell Line.

Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1 substrate) plays a critical role in the microglial inflammatory response. To confirm this hypothesis, we used lipopolysaccharide (LPS)-and interferon-gamma (IFN-γ)-induced human microglia HMC3 cells as a representative indicator of the microglial in vitro inflammatory response. We found that C15orf39 was down-regulated when interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) expression increased in LPS/IFN-γ-stimulated HMC3 cells. Once C15orf39 was overexpressed, IL-6 and TNFα expression were reduced in LPS/IFN-γ-stimulated HMC3 cells. In contrast, C15orf39 knockdown promoted IL-6 and TNFα expression in LPS/IFN-γ-stimulated HMC3 cells. These results suggest that C15orf39 is a suppressive factor in the microglial inflammatory response. Mechanistically, C15orf39 interacts with the cytoplasmic protein arginine methyltransferase 2 (PRMT2). Thus, we termed C15orf39 a PRMT2 interaction protein (PRMT2 IP). Furthermore, the interaction of C15orf39 and PRMT2 suppressed the activation of NF-κB signaling via the PRMT2-IκBα signaling axis, which then led to a reduction in transcription of the inflammatory factors IL6 and TNF-α. Under inflammatory conditions, NF-κBp65 was found to be activated and to suppress C15orf39 promoter activation, after which it canceled the suppressive effect of the C15orf39-PRMT2-IκBα signaling axis on IL-6 and TNFα transcriptional expression. In conclusion, our findings demonstrate that in a steady condition, the interaction of C15orf39 and PRMT2 stabilizes IκBα to inhibit IL-6 and TNFα expression by suppressing NF-κB signaling, which reversely suppresses C15orf39 transcription to enhance IL-6 and TNFα expression in the microglial inflammatory condition. Our study provides a clue as to the role of C15orf39 in microglia-mediated inflammation, suggesting the potential therapeutic efficacy of C15orf39 in some central nervous system diseases.

Development and characterization of an antibody that recognizes influenza virus N1 neuraminidases.

Influenza A viruses (IAVs) continue to pose a huge threat to public health, and their prevention and treatment remain major international issues. Neuraminidase (NA) is the second most abundant surface glycoprotein on influenza viruses, and antibodies to NA have been shown to be effective against influenza infection. In this study, we generated a monoclonal antibody (mAb), named FNA1, directed toward N1 NAs. FNA1 reacted with H1N1 and H5N1 NA, but failed to react with the NA proteins of H3N2 and H7N9. In vitro, FNA1 displayed potent antiviral activity that mediated both NA inhibition (NI) and blocking of pseudovirus release. Moreover, residues 219, 254, 358, and 388 in the NA protein were critical for FNA1 binding to H1N1 NA. However, further validation is necessary to confirm whether FNA1 mAb is indeed a good inhibitor against NA for application against H1N1 and H5N1 viruses.

5-HT7R enhances neuroimmune resilience and alleviates meningitis by promoting CCR5 ubiquitination.

INTRODUCTION: Excessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear. OBJECTIVES: Here we found a neuroimmune way that prevents infection-induced tissue damage. METHODS: By FACS and histopathology analysis of brain Streptococcus pneumonia meningitis infection model and behavioral testing. Western blot, co-immunoprecipitation, and ubiquitination analyze the Fluoxetine initiate 5-HT7R-STUB1-CCR5 K48-linked ubiquitination degradation. RESULTS: Fluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HT7R, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HT7R axis induces proteasome-dependent degradation of CCR5 via mTOR signaling, and then recruits STUB1, an E3 ubiquitin ligase, to initiate K48-linked polyubiquitination of CCR5 at K138 and K322, promotes its proteasomal degradation. STUB1 deficiency blocks 5-HT7R-mediated CCR5 degradation. CONCLUSION: Our results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HT7R-CCR5 axis as a potential target to promote neuroimmune resilience.

Causal link between gut microbiome and schizophrenia: a Mendelian randomization study.

OBJECTIVE: Some observational studies have shown that gut microbiome is significantly changed in patients with schizophrenia. We aim to identify the genetic causal link between gut microbiome and schizophrenia. METHODS: A two-sample Mendelian randomization (MR) study was used to evaluate the causal link between gut microbiome and schizophrenia with 28 gut microbiome-associated genetic instrumental variants chosen from recent MR reports and the largest schizophrenia genome-wide association studies (8-Apr-22 release). RESULTS: Inverse variance weighted method showed that genetically increased Bacteroidales_S24-7 (per SD) resulted in increased risk of schizophrenia (OR = 1.110, 95% CI: [1.012-1.217], P  = 0.027). Similarly, genetically increased Prevotellaceae promoted schizophrenia risk (OR = 1.124, 95% CI: [1.030-1.228], P  = 0.009). However, genetically increased Lachnospiraceae reduced schizophrenia risk (OR = 0.878, 95% CI: [0.785-0.983], P  = 0.023). In addition, schizophrenia risk was also suppressed by genetically increased Lactobacillaceae (OR = 0.878, 95% CI: [0.776-0.994], P  = 0.040) and Verrucomicrobiaceae (OR = 0.860, 95% CI: [0.749-0.987], P  = 0.032). Finally, we did not find any significant results in the causal association of other 23 gut microbiome with schizophrenia. CONCLUSION: Our analysis suggests that genetically increased Bacteroidales_S24-7 and Prevotellaceae promotes schizophrenia risk, whereas genetically increased Lachnospiraceae, Lactobacillaceae, and Verrucomicrobiaceae reduces schizophrenia risk. Thus, regulation of the disturbed intestinal microbiota may represent a new therapeutic strategy for patients with schizophrenia.

Mendelian randomization study on causal association of FAM210B with drug-induced lupus.

OBJECTIVE: Due to the complexity of drug-induced lupus (DIL) pathogenesis, more susceptibility factors need to be discovered. FAM210B is a new mitochondrial protein whose function has not been fully elucidated. This study will explore whether there is a correlation between FAM210B and the risk of DIL. METHODS: At first, we extracted three FAM210B genetic variants from the GTEx database (n = 948), and extracted their corresponding genome-wide association study (GWAS) summary statistics from DIL (101 DIL cases and 218691 controls). Then, we performed a Mendelian randomization (MR) study to evaluate the causal association of the expression of FAM210B with DIL using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. RESULTS: We successfully extracted three FAM210B single-nucleotide polymorphisms (SNPs) (rs116032784, rs34361943 and rs33923703) from the GTEx_Analysis_v8_eQTL data that can reduce FAM210B expression. The results of the MR analysis showed that genetically reduced expression of FAM210B was significantly associated with increased risk of DIL in European ancestry based on the IVW method (ß = 1.037, p = 0.001, odds ratio [OR] = 2.821, 95% confidence interval [CI]:1.495-5.322). CONCLUSION: MR analysis showed a causal relationship between FAM210B expression and the risk of DIL disease. Our results suggested that FAM210B may be a marker that can mark susceptibility of DIL in the future. It provides evidence for the study of DIL, but its specific mechanism of action in DIL needs to be further studied. Key Points •This is the first MR analysis to examine the association between FAM210B and DIL. •The findings of this study suggested that reduced FAM210B expression is associated with the increased risk of DIL. •FAM210B may be a marker that can mark susceptibility of DIL in the future.