Modulating inflammasome activity and inflammation in the central nervous system
Compositions and methods for reducing inflammation in the central nervous system (CNS) of a mammal that has been subjected to a stroke, traumatic injury to the CNS such as traumatic brain injury (TBI), spinal cord injury (SCI), or having an autoimmune or CNS disease have been developed. The compositions and methods described herein include antibodies that specifically bind to at least one component (e.g., ASC, NALP1) in a mammalian inflammasome (e.g., the NALP1 inflammasome) and have use as treatments for SCI, TBI, stroke, and autoimmune and CNS diseases in a mammal. In a rodent model of SCI, therapeutic neutralization of ASC using a polyclonal antibody that specifically binds to ASC inhibited the inflammasome, reduced caspase-1 activation, XIAP cleavage, and interleukin processing, resulting in significant tissue sparing and functional improvement. Additionally, in a rodent model of TBI, neutralization of ASC after TBI reduced caspase-1 activation and XIAP cleavage. Further, in a rodent thromboembolic stroke model, neutralization of NLRP1 resulted in reduced histopathological damage in mice and reduced cytokine activation, suggesting that the inflammasome complex forms in the brain after stroke and is a therapeutic target for reducing the detrimental consequences of post-stroke inflammation.
1. A method of treating inflammation associated with a central nervous system (CNS) injury in a patient in need thereof, comprising:
administering to the neurons in the CNS of said patient an antibody that specifically binds to at least one intracellular component of a mammalian inflammasome,
wherein the antibody is administered intravenously, intraperitoneally or intracerebroventricularly,
and wherein said inflammation in said patient is treated.
2. The method of claim 1 , wherein said CNS injury is selected from the group consisting of traumatic brain injury (TBI), stroke and spinal cord injury (SCI).
3. The method of claim 2 , wherein the CNS injury is SCI and administering the antibody results in a decreased spinal cord lesion volume in the patient.
4. The method of claim 2 , wherein the CNS injury is stroke and administering the antibody results in a reduced infarct size in the patient.
5. The method of claim 1 , wherein administering the antibody results in improvement in motor skills and locomotor function or cognition in the patient.
6. The method of claim 1 , wherein said intracellular inflammasome component is Apoptosis-associated Spec-like protein containing a Caspase Activating Recruitment Domain (ASC) or Nacht Leucine-Rich-Repeat Protein 1 (NALP1).
7. The method of claim 6 , wherein the antibody binds to an amino acid sequence having at least 85% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO:3, and SEQ ID NO: 4.
8. The method of claim 1 , wherein said antibody is taken up by said neurons in the CNS.
9. The method of claim 8 , wherein said antibody is taken up by a carbenoxolone-sensitive mechanism.
10. The method of claim 1 , wherein the administration of the antibody results in inhibition of inflammasome activation in the patient.
11. The method of claim 1 , wherein the administration of the antibody results in a reduction of caspase-1 activation and X-Linked Inhibitor of Apoptosis (XIAP) cleavage in the CNS of said patient.
12. The method of claim 1 , wherein said antibody is formulated with a pharmaceutically acceptable carrier or diluent.
13. The method of claim 1 , further comprising measuring at least one functional outcome selected from the group consisting of reduced histopathological damage, reduced cytokine activation, and reduced infarct size.