Catherine Hering

Introduction:

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide, with significant prevalence among the elderly^1,2. TBI treatment is limited, and many survivors suffer long-term disabilities, including dementia and depression^1,2,3,4. TBI causes secondary inflammatory injuries mediated by the transformation of microglia into proinflammatory phenotypes by damage-associated molecular patterns (DAMPs)¹. DAMPs trigger NLRP3 (NOD-like receptor Family Pyrin Domain Containing 3) inflammasome formation inside microglia, activating its effector protein caspase-1 to cleave IL-1β and IL-18 to active forms, which then stimulate inflammatory cascades and pyroptosis¹. Beyond TBIs, NLRP3 inflammasomes have been implicated in Parkinson’s disease and Alzheimer’s disease, making them key research targets^1,2. Microglia require colony-stimulating factor 1 receptor (CSF1R) signaling to survive, and studies have shown that brief use and withdrawal of CSF1R inhibitors restored normal microglia populations¹. Therefore, Henry and associates investigated whether short-term elimination of activated microglia by treatment with CSF1R inhibitor PLX5622 during chronic TBI, followed by repopulation, could mitigate long-term deficits¹. Methods: The study investigated the effects of microglial depopulation and repopulation on motor and cognitive function. For this, sham or controlled cortical impact (CCI) groups were given either the CSF1R inhibitor PLX5622 containing chow or standard chow. The mice were given a standard chow for microglia repopulation, then subjected to cognitive and motor function tests¹. Results: TBI significantly decreased performance on beam walk (coordination), Y-maze (spontaneous alteration), and Morris Water Test (hippocampus-dependent spatial memory), but PLX5622 treatment significantly improved performance¹. PLX5622 treatment also significantly reduced lesion size and neuronal loss¹. Real-time PCR studies demonstrated that PLX5622 significantly reduced NLRP3 inflammasome genes Nlrp3, Casp1, and Il1b¹. Nanostring analysis quantifying mRNA transcripts revealed that PLX5622 treatment significantly reduced NLRP3, caspase-1, and IL-1β mRNA levels¹. To examine NLRP3 inflammasome activity, they measured caspase-1 and IL-1β levels in microglia and found that while TBI significantly increased these levels, PLX5622 decreased them. Conclusion: Removal of activated microglia decreased NLRP3 inflammasome activation, leading to diminished proinflammatory end products like IL-1β, which improved cognitive function and decreased tissue damage¹. A limitation of this study was that only one end-product of NLRP3 inflammasome activation was measured instead of both IL-1β and IL-18¹. Overall, clinical use of CSF1R inhibitors holds promise for TBI and other diseases¹. However, microglial depletion has been shown to have adverse side effects, including neurotoxicity and off-target effects. Therefore additional research is required before CSF1R inhibitors can be considered a viable therapeutic in the clinic¹.

1. Henry RJ, Ritzel RM, Barrett JP, et al. Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits. J Neurosci. 2020;40(14):2960-2974. doi:10.1523/JNEUROSCI.2402-19.2020
2. O’Brien WT, Pham L, Symons GF, Monif M, Shultz SR, McDonald SJ. The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target. J Neuroinflammation. 2020;17(1):104. Published 2020 Apr 6. doi:10.1186/s12974-020-01778-5
3. Brett BL, Gardner RC, Godbout J, Dams-O’Connor K, Keene CD. Traumatic Brain Injury and Risk of Neurodegenerative Disorder. Biol Psychiatry. 2022;91(5):498-507. doi:10.1016/j.biopsych.2021.05.025
4. Bolte AC, Lukens JR. Neuroimmune cleanup crews in brain injury. Trends Immunol. 2021;42(6):480-494. doi:10.1016/j.it.2021.04.003
5. Trudler D, Nazor KL, Eisele YS, et al. Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc Natl Acad Sci U S A. 2021;118(15):e2025847118. doi:10.1073/pnas.2025847118
6. Pike AF, Longhena F, Faustini G, et al. Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson’s disease. J Neuroinflammation. 2022;19(1):50. Published 2022 Feb 16. doi:10.1186/s12974-022-02410-4
7. Chen Y, Gong K, Guo L, et al. Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury. Cell Death Discov. 2021;7(1):290. Published 2021 Oct 12. doi:10.1038/s41420-021-00686-8
8. Kuwar R, Rolfe A, Di L, et al. A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury. J Neuroinflammation. 2019;16(1):81. Published 2019 Apr 11. doi:10.1186/s12974-019-1471-y