Weekly Research News Digest
This newsletter is designed to share with you research news in various fields where applications of gene sequencing can be found. It will share research findings from Novogene’s customers. By sharing insights from the most prestigious research teams, it is intended to call your attention to the latest applications of sequencing in life sciences and biomedical research and inspire your research.
Welcome to the Weekly Research News Digest! In this issue, we have selected five articles focusing on the molecular mechanisms of intercellular communication and immune regulation in human diseases. In these studies, researchers employed multi-omics approaches, including transcriptomics, metabolomics, and proteomics, to explore activities and interactions at the cellular and molecular levels. The findings validate how complex intercellular communication drives immune response balance, uncover potential molecular targets in various diseases, and offer new perspectives for immune-regulation therapies.
BRD4-Dependent Macrophage-Fibroblast Communication via IL-1β Drives Fibrosis in Heart Failure
Chronic inflammation and tissue fibrosis contribute to organ dysfunction, but the molecular mechanisms underlying their interaction remain poorly understood. In a study published in Nature, researchers from the United States examined the role of Brd4 in fibrosis in heart failure using conditional gene deletion. They found that deleting Brd4 in infiltrating Cx3cr1+ macrophages improved heart failure in mice and significantly reduced fibroblast activation. By analyzing chromatin accessibility and BRD4 occupancy at the single-cell level, they revealed a large enhancer near interleukin-1β (IL-1β). With the help of CRISPR-based deletions, they identified the stress-dependent element that controls Il1b expression. IL-1β secreted by macrophages activated a fibroblast enhancer near MEOX1, promoting a profibrotic response in human cardiac fibroblasts. In vivo, neutralizing IL-1β improved cardiac function and alleviated tissue fibrosis in heart failure. Systemic inhibition of IL-1β or targeted deletion of Il1b in Cx3cr1+ cells prevented stress-induced Meox1 expression and fibroblast activation. These findings suggest that BRD4-dependent macrophage-fibroblast communication via IL-1β plays a crucial role in fibrosis, providing potential therapeutic targets for heart disease and other inflammatory disorders.
MrgprA3 Neurons Control Immune Response to Schistosoma mansoni by Regulating the Expression of Cytokine in Mice
Skin barrier integrity and immune responses depend on complex cellular networks, but the underlying mechanisms are not fully understood. A research team composed of researchers from the United States and the Czech Republic examined how Schistosoma mansoni influences pruritus and immune responses in mice. They discovered that MrgprA3 neurons controlled anti-helminth immunity by regulating the expression of cytokines in macrophages and dendritic cells. This signaling pathway facilitated the expansion of IL-17+ γδ T cells and epidermal hyperplasia, thereby enhancing skin immunity against parasitic invasion. These findings uncover a novel immune communication axis that connects sensory neurons and immune cells, which could provide new insights into host defense mechanisms.
MDM2 Regulates Glycolytic and Inflammatory Responses in M1 Macrophages in Mice
M1 macrophages play a crucial role in immunity against infection, but are also implicated in metabolic and inflammatory diseases. Researchers from various regions in China, including Hong Kong, Beijing, and Shanghai, jointly reported that the E3 ubiquitin ligase MDM2 enhances glycolytic and inflammatory activities in M1 macrophages by promoting the production of IL-1β, MCP-1, and NO. Mechanistically, MDM2 facilitates the ubiquitination and degradation of the E3 ligase SPSB2, which stabilizes iNOS and boosts NO production. This, in turn, leads to the S-nitrosylation and activation of HIF-1α, triggering glycolytic and pro-inflammatory pathways in M1 macrophages. When MDM2 is deleted specifically in myeloid cells in mice, it reduces LPS-induced endotoxemia, NO production, and inflammation in adipose tissue-resident macrophages caused by obesity. On the other hand, MDM2 haplodeletion results in increased mortality, tissue damage, bacterial load, and a suppressed M1 macrophage response in a sepsis model induced by cecal ligation and puncture. These findings highlight MDM2's role in modulating inflammatory responses, suggesting new therapeutic targets for inflammatory diseases.
Targeting Immunoproteasome in Macrophages: A Novel Therapeutic Strategy for COPD
Chronic obstructive pulmonary disease (COPD) lacks effective treatments, and immunoproteasome inhibition has shown promise in other inflammatory diseases. A recent study published in Advanced Science examined the effects of the immunoproteasome inhibitor ONX-0914 on COPD in macrophages from mice with LPS/Elastase-induced emphysema and in polarized macrophages cultured in vitro. The researchers found that ONX-0914 significantly reduced airway inflammation and improved lung function by inhibiting macrophage polarization. Mechanistically, ONX-0914 supressed M1 polarization through the NRF1/NRF2-P62 axis and inhibited M2 polarization by suppressing the transcription of IRF4. These results highlight the potential of targeting immunoproteasome in macrophages as a novel therapeutic strategy for COPD.
Regulation of Skin Inflammation and Lipid Metabolism by m6A Modification in Keratinocytes
Disrupted N6-methyladenosine (m6A) modification is implicated in various inflammatory disorders, though its role in skin inflammation remains unclear. Researchers explored the effects of m6A and its methyltransferase METTL3 on skin inflammation. They found that deleting Mettl3 in murine keratinocytes triggers spontaneous skin inflammation and increases susceptibility to skin inflammation by promoting neutrophil recruitment. Restoring m6A mitigates disease symptoms in mice and reduces inflammation in human biopsy specimens. The researchers proposed a model in which m6A modification corrects lipid metabolism by stabilizing the mRNA of the lipid-metabolizing enzyme ELOVL6, reducing palmitic acid accumulation, and suppressing neutrophil chemotaxis. This study highlights the crucial role of m6A in regulating lipid metabolism and immune responses, suggesting potential therapeutic strategies for inflammatory skin diseases.
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Novogene specializes in the application of advanced molecular biotechnology and high-performance computing in the research fields of life science and human health. Established in March 2011, Novogene strives to become a global leader in providing genetic science services and technology products. Novogene has set up operations and laboratories in the United States, the United Kingdom, Netherlands, Germany, as well as in China, Singapore and Japan.
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