Microglial heparan sulfate proteoglycans facilitate the cluster-of-differentiation 14 (CD14)/Toll-like receptor 4 (TLR4)-dependent inflammatory response [Immunology]

April 13th, 2015 by O'Callaghan, P., Li, J.-P., Lannfelt, L., Lindahl, U., Zhang, X.

Microglia rapidly mount an inflammatory response to pathogens in the central nervous system (CNS). Heparan sulfate proteoglycans (HSPGs) have been attributed various roles in inflammation. To elucidate the relevance of microglial HSPGs in a pro-inflammatory re-sponse we isolated microglia from mice over-expressing heparanase (Hpa-tg), the HS-degrading endoglucuronidase, and challenged them with lipopolysaccharide (LPS), a bacte-rial endotoxin. Prior to LPS-stimulation, the LPS-receptor cluster-of-differentiation 14 (CD14) and toll-like receptor 4 (TLR4; essen-tial for the LPS response) were similarly ex-pressed in Ctrl and Hpa-tg microglia. Howev-er, compared to Ctrl microglia, Hpa-tg cells released significantly less tumor necrosis fac-tor-α (TNFα), essentially failed to upregulate interleukin-1β (IL1β) and did not initiate syn-thesis of proCD14. Isolated primary astroyc-tes expressed TLR4, but notably lacked CD14 and in contrast to microglia, LPS challenge induced a similar TNFα response in Ctrl and Hpa-tg astrocytes, while neither released IL1β. The astrocyte TNFα-induction was thus attributed to CD14-independent TLR4 activation and was unaffected by the cells HS status. Equally, the suppressed LPS-response in Hpa-tg microglia indicated a loss of CD14-dependent TLR4 activation, suggesting that microglial HSPGs facilitate this process. In-deed, confocal microscopy confirmed interac-tions between microglial HS and CD14 in LPS-stimulated microglia and a potential HS-binding motif in CD14 was identified. We conclude that microglial HSPGs facilitate CD14-dependent TLR4 activation and that heparanase can modulate this mechanism.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Microglial heparan sulfate proteoglycans facilitate the cluster-of-differentiation 14 (CD14)/Toll-like receptor 4 (TLR4)-dependent inflammatory response [Immunology]