Increased Monocyte Chemotactic Protein-1 Accompanying Pro-Inflammatory Processes are Associated with Progressive Hearing Impairment and Bilateral Disability of Meniere’s Disease

<b><i>Background:</i></b> The progression of hearing impairment and the bilateral involvement of Meniere’s disease (MD) may depend on the disease duration and aging. Recent studies reported that MD might involve dysfunction of the microvascular circulation damaged due to inflammatory changes. <b><i>Objectives:</i></b> The aim of this study was to determine that the progress of the MD’s hearing impairment and bilateral disability may be associated with the pathogenesis of several pro-inflammatory processes. <b><i>Patients and Methods:</i></b> We recruited 30 unilateral MD patients (56.8 ± 14.7 years old), 7 bilateral MD patients (65.3 ± 13.9 years old), and 17 age-matched control subjects (53.5 ± 14.4 years old, <i>p</i> &#x3e; 0.05). We measured the plasma vascular endothelial growth factor (VEGF), plasma interleukin-6 (IL-6), plasma tumor-necrosis factor α (TNFα), and plasma monocyte chemotactic protein-1 (MCP-1). <b><i>Results:</i></b> The bilateral MD group and the unilateral MD group had higher plasma MCP-1 (204.7 ± 41.0 pg/mL and 169.5 ± 32.0 pg/mL) than the control group (149.2 ± 30.7 pg/mL) (<i>p</i> &#x3c; 0.05). There was no significant difference in plasma TNFα, IL-6, and VEGF among 3 groups (<i>p</i> &#x3e; 0.05). There was a strong correlation between the plasma MCP-1 and age in MD patients (<i>r</i> = 0.58, <i>p</i> &#x3c; 0.01); however, no significant correlation between the plasma MCP-1 and age was found in control subjects (<i>p</i> &#x3e; 0.05). The plasma MCP-1 significantly correlated with the average hearing level of 500, 1,000, 2,000, and 4,000 Hz, and the maximum slow phase eye velocity in caloric test in the better side (<i>p</i> &#x3c; 0.05). Also, the plasma MCP-1 showed significant positive correlations with the plasma IL-6 (<i>r</i> = 0.49, <i>p</i> &#x3c; 0.01) and plasma TNFα (<i>r</i> = 0.32, <i>p</i> &#x3c; 0.05) in MD group. <b><i>Conclusions:</i></b> Our results suggest that the increased plasma MCP-1 accompanying pro-inflammatory processes are associated with the progression of the hearing impairment and the bilateral disability of MD.

Mammary Tumorigenesis and Metabolome in Male Adipose Specific Monocyte Chemotactic Protein-1 Deficient MMTV-PyMT Mice Fed a High-Fat Diet

Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific Mcp-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. Mcp-1-/- mice had a longer tumor latency (25.2 weeks vs. 18.0 weeks) and lower tumor incidence (19% vs. 56%), tumor progression (2317% vs. 4792%), and tumor weight (0.23 g vs. 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between Mcp-1-/- and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model.

PRRSV Nsp11 Antagonizes Broad Antiviral Effects of MCPIP1 via Inducing IL-17 Expression

Monocyte chemotactic protein-induced protein 1 (MCPIP1) is an inflammatory regulator in immune response and has broad antiviral effects by targeting viral RNA. Porcine reproductive and respiratory syndrome virus (PRRSV), a major viral pathogen in pigs, causes immune suppression leading to co-infection of swine pathogens but the mechanisms are not fully clarified. In this study, MCPIP1 expression was found to be significantly up-regulated in lungs of PRRSV-infected piglets, as well as in Marc-145 and PAM cells upon PRRSV stimulation. MCPIP1 overexpression significantly inhibited PRRSV replication while MCPIP1 knock-down increased virus titer. Various mutations in RNase functional domains of MCPIP1 impaired the inhibitory activity against PRRSV, while those in deubiquitinase domains failed to. MCPIP1 expression started to decrease from 60 h post PRRSV infection in PAMs. Meanwhile, infection with higher dose of PRRSV further down-regulated MCPIP1, indicating the antagonizing effects from PRRSV against MCPIP1. Moreover, it was confirmed that MCPIP1 expression was down-regulated in 3D4 cells with either IL-17 or nsp11 overexpression, while IL-17 inhibitor abolished the decrease of MCPIP1 caused by nsp11, indicating nsp11 employs IL-17 induction to inhibit MCPIP1. Furthermore, PRRSV nsp11 mutant with deficiency in IL-17 induction showed the recovered expression of MCPIP1 in infected cells, inspiring a strategy for virus attenuation. This is the first report about the role of MCPIP1 against PRRSV and the function of PRRSV nsp11 against innate immunity to facilitate virus replication via IL-17. The study not only illuminates PRRSV infection machinery but also enlightens alternative antiviral strategies, such as vaccine candidates. Importance Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses the innate immunity and leads to co-infection of swine pathogens. Monocyte chemotactic protein-induced protein 1 (MCPIP1) is a broad-spectrum host antiviral protein. Therefore, to further clarify the mechanism of PRRSV against innate immunity, we explored the relationship between MCPIP1 and PRRSV infection. The results showed that MCPIP1 inhibited PRRSV infection in the early stage of virus infection. Importantly, PRRSV nsp11 subsequently employed IL-17 induction to suppress MCPIP1 expression and antagonized anti-PRRSV effects. Furthermore, PRRSV with mutation of nsp11 S74A failed to induce MCPIP1 reduction. These findings confirmed the function of MCPIP1 against swine viruses and revealed that PRRSV nsp11 plays an important role in virus against innate immunity. This study enlightens a new strategy to develop safer attenuated vaccines against PRRSV by nsp11 mutation.

Higher expression of monocyte chemotactic protein 1 in mild COVID-19 patients might be correlated with inhibition of Type I IFN signaling

Background Chemokine levels in severe coronavirus disease 2019 (COVID-19) patients have been shown to be markedly elevated. But the role of chemokines in mild COVID-19 has not yet been established. According to the epidemiological statistics, most of the COVID-19 cases in Shiyan City, China, have been mild. The purpose of this study was to evaluate the level of chemokines in mild COVID-19 patients and explore the correlation between chemokines and host immune response. Methods In this study, we used an enzyme-linked immunosorbent assay to detect serum levels of chemokines in COVID-19 patients in Shiyan City. Expression of chemokine receptors and of other signaling molecules was measured by real-time polymerase chain reaction. Results We first demonstrated that COVID-19 patients, both sever and mild cases, are characterized by higher level of chemokines. Specifically, monocyte chemotactic protein 1 (MCP-1) is expressed at higher levels both in severe and mild cases of COVID-19. The receptor of MCP-1, C-C chemokine receptor type 2, was expressed at higher levels in mild COVID-19 patients. Finally, we observed a significant negative correlation between expression levels of interferon (IFN) regulatory factor 3 (IRF3) and serum levels of MCP-1 in mild COVID-19 patients. Conclusion Higher expression of MCP-1 in mild COVID-19 patients might be correlated with inhibition of IFN signaling. The finding adds to our understanding of the immunopathological mechanisms of severe acute respiratory syndrome coronavirus 2 infection and provides potential therapeutic targets and strategies.