A novel pathway for immune-mediated axonal regeneration after SCI
Funded in: 2015, 2016, 2017, 2018
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Problem: Regeneration of the central nervous system is limited after SCI.
Target: Activation of pattern recognition receptors (Dectin-1) might lead to neural repair.
Goal: This could lead to a new strategy for drug development to promote neural repair.
Nerve cells in the brain and spinal cord form elaborate networks to communicate with each other. Following injury to the adult mammalian brain or spinal cord, some of these networks get damaged, and vital connections, called axons, are severed. Nerve cells fail to spontaneously grow and reestablish lost connections. This leads to permanent neurological deficits.
Under certain circumstances, activation of the immune system helps to promote neural tissue repair following spinal cord injury. However, the underlying cellular and molecular mechanisms of how the immune system promotes nervous tissue repair remain poorly understood. There are many different ways to activate the immune system and to trigger an inflammatory response in the CNS; induction of an anti-fungal immune response has beneficial effects on injured nerve cells. In marked contrast, induction of an anti-bacterial immune response fails to promote nerve cell regeneration. Conserved molecular structures associated with different groups of pathogens are called PAMPs (pathogen-associated molecular patterns) and are recognized by immune receptors called pattern recognition receptors (PRRs).
They recently found that activation of dectin-1, a PPR produced by many immune cells, is sufficient to promote robust regeneration of severed axons in mice. In addition to fungal PAMPs, dectin-1 binds to endogenous ligands released by host cells following tissue damage, so called “alarmins”. The goal is to identify the alarmins produced by neural tissue to activate dectin-1.
To test the role of candidate alarmins, they will inject these molecules into sensory ganglia and ask whether they promote growth of axons that have been severed by spinal cord injury. They use a mouse genetic approach to understand whether alarmins promote neural repair in a dectin-1-dependent manner. If successful, their work will lead to a better understanding of how the immune system beneficially impacts nervous tissue repair following spinal cord injury. Activation of dectin-1 signaling represents a new strategy for drug development to promote neural repair.