Endogenous CNS proteins activate destructive inflammatory macrophages after SCI via dectin-1, an anti-fungal immune receptor
Funded in: 2015, 2016, 2017, 2018
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Problem: Regeneration of the central nervous system is limited after SCI.
Target: Blocking Dectin-1 might be neuroprotective and lead to neural repair.
Goal: This approache could lead to the development of novel therapeutics.
In this proposal the project team will study a novel immune receptor, known as dectin-1, that participates in regulating CNS macrophage function after spinal cord injury. Research shows that zymosan, a component of fungal cell walls, simultaneously activates growth promoting and neurotoxic effector functions in CNS macrophages. It does this by binding to toll-like receptor 2 (TLR2) and dectin-1 receptor.
The project team and others have shown that recovery of function and axonal growth after spinal cord injury (SCI) are positively influenced by TLR2 activation. However, the effects of dectin-1 signaling have not been determined in the CNS. The overall hypothesis to be tested in the current proposal is that “danger-associated molecular patterns” (DAMPs) released at the site of SCI activate myeloid cells (microglia and macrophages) via dectin-1 and trigger effector functions that cause secondary injury or prevent axon regeneration and tissue repair; blocking dectin-1 signalling will be neuroprotective and enhance recovery after SCI. As such, inhibiting this receptor in vivo could have therapeutic value.
Using a co-immunoprecipitation and proteomics approach we will identify and characterize the effects of novel endogenous CNS ligands that activate neurotoxic effects in microglia/macrophages by binding to dectin-1. Two different forms of dectin-1 inhibition (WGP soluble (whole glucan particles), which is a dectin-1 blocking molecule, and dectin-1 blocking antibody) will be used to test if they can limit the neurotoxic potential of dectin-1 activated macrophages in vitro and in vivo. If successful, both approaches could lead to the development of novel therapeutics.