The early macrophage response to pathogens requires dynamic regulation of the nuclear paraspeckle
Sikandar Azam1, Kaitlyn S Armijo1, Chi G Weindel1
1Department of Microbial Pathogenesis and Immunology, Texas A&M University, School of Medicine, Bryan, TX 77807.
Abstract:
To ensure a robust immune response to pathogens without risking immunopathology, the kinetics and amplitude of inflammatory gene expression in macrophages need to be exquisitely well controlled. There is a growing appreciation for stress-responsive membraneless organelles (MLOs) regulating various steps of eukaryotic gene expression in response to extrinsic cues. Here, we implicate the nuclear paraspeckle, a highly ordered biomolecular condensate that nucleates on the Neat1 lncRNA, in tuning innate immune gene expression in murine macrophages. In response to a variety of innate agonists, macrophage paraspeckles rapidly aggregate (0.5 h poststimulation) and disaggregate (2 h poststimulation). Paraspeckle maintenance and aggregation require active transcription and MAPK signaling, whereas paraspeckle disaggregation requires degradation of Neat1 via the nuclear RNA exosome. In response to lipopolysaccharide treatment, Neat1 KO macrophages fail to properly express a large cohort of proinflammatory cytokines, chemokines, and antimicrobial mediators. Consequently, Neat1 KO macrophages cannot control replication of Salmonella enterica serovar Typhimurium or vesicular stomatitis virus. These findings highlight a prominent role for MLOs in orchestrating the macrophage response to pathogens and support a model whereby dynamic assembly and disassembly of paraspeckles reorganizes the nuclear landscape to enable inflammatory gene expression following innate stimuli.
Insights
Nuclear paraspeckles, regulated by Neat1 lncRNA, control inflammatory gene expression in macrophages. Their dynamic assembly and disassembly are crucial for mounting effective immune responses against pathogens.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Macrophage inflammatory gene expression requires precise control to balance pathogen defense and prevent self-damage.
- Membraneless organelles (MLOs) are increasingly recognized for regulating gene expression in response to cellular stress.
- Nuclear paraspeckles, MLOs formed around the Neat1 lncRNA, are implicated in gene regulation.
Purpose of the Study:
- To investigate the role of nuclear paraspeckles and Neat1 lncRNA in regulating innate immune responses in macrophages.
- To elucidate the mechanisms controlling paraspeckle dynamics during innate immune activation.
- To determine the functional consequences of paraspeckle dysfunction on macrophage antimicrobial activity.
Main Methods:
- Studied paraspeckle dynamics (aggregation and disaggregation) in murine macrophages following stimulation with innate agonists.
- Investigated the molecular requirements for paraspeckle maintenance and disassembly, including transcription and MAPK signaling.
- Utilized Neat1 knockout (KO) macrophages to assess the impact on gene expression and pathogen control.
Main Results:
- Macrophage paraspeckles exhibit rapid, stimulus-dependent aggregation and disaggregation.
- Paraspeckle dynamics are dependent on active transcription, MAPK signaling, and Neat1 degradation via the RNA exosome.
- Neat1 KO macrophages show impaired expression of key inflammatory genes and reduced ability to control Salmonella and vesicular stomatitis virus replication.
Conclusions:
- Nuclear paraspeckles play a critical role in orchestrating the macrophage innate immune response.
- Dynamic assembly and disassembly of paraspeckles are essential for timely and appropriate inflammatory gene expression.
- MLOs like paraspeckles are key regulators of the nuclear landscape, enabling effective host defense against pathogens.
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