Human microglia express anti-inflammatory ISG15 in response to Neisseria meningitidis

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.