The Contributions of CD74 to Acquired Epilepsy
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abstract
Traumatic brain injury (TBI) constitutes ~15-20% of symptomatic epilepsies and ~5% of all epilepsy cases. These acquired epilepsies are amongst the hardest to treat and are often resistant to first- and second-line anti-epileptic treatments. Preventing the acquisition of epilepsy after injury is vital to improving outcomes this patient population. We have discovered that following a TBI, there is an increase in the frequency and activation state of peripheral immune cells. Identification of subsets of these expanded and activated immune cells revealed cell-surface markers that indicate a transition from an innate to an adaptive immune response occurs after TBI. Thus, targeting the innate and/or the adaptive immune response could alter the epileptogenic progression following a TBI. We further discovered that antagonizing or deleting CD74 is neuroprotective after a TBI. Full-length CD74 is involved in the innate immune response, whereas cleavage of full-length CD74 into CLIP is involved in the transition from an innate to an adaptive immune response. Considering our findings and the fact that CD74 has distinct and important functions in both, the innate and the adaptive immune response, we hypothesize that targeting specific CD74 functions will attenuate the acquisition of epilepsy after a TBI. To test our hypothesis, we have designed a series of experiments that selectively manipulate full-length CD74 (Aim 1), or its cleavage product, CLIP (Aim 2), and examine their respective rolesin the acquisition of epilepsy. Aim 1: Experiment 1: Determine if genetic deficiency of CD74 attenuates the acquisition of post-traumatic epilepsy (PTE). Experiment 2: MIF is soluble ligand for the full-length cell surface form of CD74 that is involved in initiating the innate immune, pro-inflammatory CD74 signaling events. We will block MIF-binding to CD74 and test if this antagonism will alter seizure threshold, and prevent the acquisition of PTE. Experiment 3. Prevent the proteolytic cleavage of CD74 into CLIP, to test the effects of full-length, intact CD74, in the absence of CLIP, on the acquisition of PTE. Mice will be exposed to TBI followed immediately after by treatment with cystatins, protease inhibitors that inhibit cleavage of CD74.Aim 2: Experiment 4. For this experiment, we will administer our bioengineered CLIP antagonist after TBI and assess seizure threshold and the acquisition of PTE.Experiments 5 & 6. In experiments 5 and 6, we will determine if seizure susceptibility is exacerbated by replacing CLIP in mice in which CLIP has been depleted. In Experiment 5, we will administer exogenous synthetic CLIP to CD74 deficient mice, and in Experiment 6, we will administer exogenous CLIP to WT mice treated with cystatins that prevent the cleavage of CD74 into CLIP. These experiments will elucidate the role(s) of CD74 in the acquisition of PTE.
