A variety of innate immune responses and functions are dependent on time of day, and many inflammatory conditions are associated with dysfunctional molecular clocks within immune cells. However, the functional importance of these innate immune clocks has yet to be fully characterized. NRF2 plays a critical role in the innate immune system, limiting inflammation via reactive oxygen species (ROS) suppression and direct repression of the proinflammatory cytokines, IL-1β and IL-6. Here we reveal that the core molecular clock protein, BMAL1, controls the mRNA expression of via direct E-box binding to its promoter to regulate its activity. Deletion of decreased the response of NRF2 to LPS challenge, resulting in a blunted antioxidant response and reduced synthesis of glutathione. ROS accumulation was increased in macrophages, facilitating accumulation of the hypoxic response protein, HIF-1α. Increased ROS and HIF-1α levels, as well as decreased activity of NRF2 in cells lacking BMAL1, resulted in increased production of the proinflammatory cytokine, IL-1β. The excessive prooxidant and proinflammatory phenotype of macrophages was rescued by genetic and pharmacological activation of NRF2, or through addition of antioxidants. Our findings uncover a clear role for the molecular clock in regulating NRF2 in innate immune cells to control the inflammatory response. These findings provide insights into the pathology of inflammatory conditions, in which the molecular clock, oxidative stress, and IL-1β are known to play a role.
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http://dx.doi.org/10.1073/pnas.1800431115 | DOI Listing |
Curr Cardiol Rep
January 2025
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St. Louis, MO, 63110, USA.
Purpose Of Review: This review aims to explore the role of immune memory and trained immunity, focusing on how innate immune cells like monocytes, macrophages, and natural killer cells undergo long-term epigenetic and metabolic rewiring. Specifically, it examines the mechanisms by which trained immunity, often triggered by infection or vaccination, could impact cardiac processes and contribute to both protective and pathological responses within the cardiovascular system.
Recent Findings: Recent research demonstrates that vaccination and infection not only activate immune responses in circulating monocytes and tissue macrophages but also affect immune progenitor cells within the bone marrow environment, conferring lasting protection against heterologous infections.
J Gen Virol
January 2025
Division of Infection and Immunity, UCL, London, WC1E 6BT, UK.
Human immunodeficiency virus (HIV) is an exemplar virus, still the most studied and best understood and a model for mechanisms of viral replication, immune evasion and pathogenesis. In this review, we consider the earliest stages of HIV infection from transport of the virion contents through the cytoplasm to integration of the viral genome into host chromatin. We present a holistic model for the virus-host interaction during this pivotal stage of infection.
View Article and Find Full Text PDFMicrobiol Spectr
January 2025
Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
Unlabelled: Group A (GAS) is a major human pathogen that causes several invasive diseases including necrotizing fasciitis. The host coagulation cascade initiates fibrin clots to sequester bacteria to prevent dissemination into deeper tissues. GAS, especially skin-tropic bacterial strains, utilize specific virulence factors, plasminogen binding M-protein (PAM) and streptokinase (SK), to manipulate hemostasis and activate plasminogen to cause fibrinolysis and fibrin clot escape.
View Article and Find Full Text PDFmBio
January 2025
Department of Microbiology and Molecular Genetics, University of California, Davis, California, USA.
Orthoflaviviruses are positive-sense single-stranded RNA viruses that hijack host proteins to promote their own replication. Zika virus (ZIKV) is infamous among orthoflaviviruses for its association with severe congenital birth defects, notably microcephaly. We previously mapped ZIKV-host protein interactions and identified the interaction between ZIKV non-structural protein 4A (NS4A) and host microcephaly protein ankyrin repeat and LEM domain-containing 2 (ANKLE2).
View Article and Find Full Text PDFJ Proteome Res
January 2025
PPGEMN, School of Engineering, Mackenzie Presbyterian University & MackGraphe - Mackenzie Institute for Research in Graphene and Nanotechnologies, Mackenzie Presbyterian Institute, São Paulo, São Paulo 01302-907, Brazil.
Since late 2021, Omicron variants have dominated the epidemiological scenario as the most successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sublineages, driving new and breakthrough infections globally over the past two years. In this study, we investigated for the first time the host salivary response of COVID-19 patients infected with Omicron variants (BA.1, BA.
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