Microglial heparan sulfate proteoglycans mediate pro-inflammatory signaling
(English)Manuscript (preprint) (Other academic)
Microglia are the central nervous system’s (CNS) first line of defense against pathogenic insults and acute inflammatory responses are necessary for the resolution of infection. However, unregulated and/or chronic activation of microglia is associated with neurodegeneration. Heparan sulfate proteoglycans (HSPGs) have been attributed various roles in inflammation, but the possibility that HSPGs are integral to pro-inflammatory signaling mechanisms has not been fully explored. To analyze the relevance of microglial HSPGs in the pro-inflammatory response we isolated primary microglia from mice overexpressing human heparanase (Hpa-tg), the HS-degrading endoglucuronidase, and challenged them with the pro-inflammatory endotoxin lipopolysaccharide (LPS). The LPS-induced upregulation of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was inhibited in Hpa-tg microglia, as was upregulation of the LPS-receptor CD14. Analysis of HSPG structures revealed that Hpa-tg microglia produced truncated HS chains. Importantly, co-treatment of microglia with heparin attenuated LPS-induced cytokine upregulation. Together these findings implicate microglial HSPGs as key facilitators of the pro-inflammatory response. Astrocytes constitute a critical support network in the CNS, but are also implicated in inflammation. LPS induced comparable levels of TNF-α in Hpa-tg and Ctrl astrocytes, indicating that the mechanism of HSPG-dependent inflammation is specific to microglia. We conclude that microglial HSPGs are required for pro-inflammatory signaling events and that heparanase, through its HS-degrading activity, can regulate this mechanism.
Neurosciences Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-159923OAI: oai:DiVA.org:uu-159923DiVA: diva2:447492