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Updated: Feb 15, 2026
Neisseria meningitidis Infection of Induced Pluripotent Stem-Cell Derived Brain Endothelial Cells
Published on: July 14, 2020
Human microglia express anti-inflammatory ISG15 in response to Neisseria meningitidis
Andrew M Dunphy1, Krishna Majithia1, Quinton A Krueger1
1Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28262, USA.
Abstract:
Glial cells respond to the presence of bacteria by producing inflammatory mediators but these responses can result in damage to the central nervous system (CNS). However, glia can also produce immunosuppressive mediators that can serve to mitigate such effects. Here, we demonstrate that human microglial cells and, to a lesser extent, primary human astrocytes, can express and secrete interferon stimulated gene 15 (ISG15) in response to a clinically relevant CNS pathogen, Neisseria meningitidis, and ligands for Toll-like receptor 4 (TLR4) that include lipopolysaccharide and lipooligosaccharide derived from N. meningitidis. Exogenous ISG15 failed to elicit human neutrophil-like cell migration and induce or augment their inflammatory responses. Similarly, recombinant ISG15 application did not elicit inflammatory cytokine or chemokine production by either human microglial cells or astrocytes, and did not augment their responses to TLR stimulation or N. meningitidis infection. Rather, ISG15 treatment limited N. meningitidis-induced NF-κB activation and associated inflammatory cytokine production by these cells, perhaps via a non-canonical TLR-mediated pathway. These observations may be indictive of a novel negative feedback loop whereby the recognition of bacterial motifs precipitates ISG15 expression by resident microglia that subsequently mitigates further neuroinflammatory responses.
Insights
Glial cells, like microglia, produce interferon stimulated gene 15 (ISG15) in response to Neisseria meningitidis. This ISG15 may mitigate neuroinflammation by limiting inflammatory responses in the central nervous system (CNS).
Area of Science:
- Neuroimmunology
- Cellular Biology
- Infectious Disease
Background:
- Glial cells initiate inflammatory responses to pathogens in the central nervous system (CNS), potentially causing damage.
- Glial cells can also produce immunosuppressive mediators to mitigate these harmful effects.
Purpose of the Study:
- To investigate the role of interferon stimulated gene 15 (ISG15) in glial cell responses to Neisseria meningitidis and Toll-like receptor 4 (TLR4) stimulation.
- To determine if ISG15 modulates neuroinflammatory responses mediated by human microglia and astrocytes.
Main Methods:
- Human microglial cells and primary human astrocytes were stimulated with Neisseria meningitidis and TLR4 ligands (lipopolysaccharide, lipooligosaccharide).
- Expression and secretion of ISG15 were analyzed.
- The effects of exogenous ISG15 on neutrophil migration and inflammatory responses of glial cells were assessed.
- NF-κB activation and cytokine production in response to ISG15 treatment were measured.
Main Results:
- Human microglia and astrocytes express and secrete ISG15 upon stimulation with Neisseria meningitidis and TLR4 ligands.
- Exogenous ISG15 did not induce neutrophil migration or inflammatory cytokine production by glial cells.
- ISG15 treatment suppressed Neisseria meningitidis-induced NF-κB activation and inflammatory cytokine production in microglia and astrocytes.
Conclusions:
- Glial cells, particularly microglia, produce ISG15 in response to bacterial stimuli.
- ISG15 acts as a negative feedback mechanism, mitigating neuroinflammatory responses by limiting NF-κB activation and cytokine release.
- This suggests a novel pathway for regulating neuroinflammation in the CNS.
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