Marita John

 Introduction: Traumatic brain injury (TBI) is one of the major causes of morbidity and mortality worldwide.¹ The hallmarks of TBI include cognitive dysfunction and activated microglia, but it is unclear whether activated microglia are harmful or beneficial. Recent studies have investigated whether manipulating the activation of microglia or its ablation would result in improved recovery in a mouse model of TBI^2,3. The studies also addressed if short-term microglial elimination followed by repopulation would impact neuroinflammation or brain recovery following TBI.^2,4,5  Methods: TBI was inflicted in the mouse model using a controlled cortical impact. Next, microglia positive for IBA-1 and TMEM119 were depleted using a diet containing CSF-1R antagonist PLX5622.⁶ . The cognitive function of mice was tested using an active place avoidance (APA) test, a behavioral paradigm that relies on hippocampal function.² A genetic model, CX₃CR1cre^ERT2 x iDTR, was also employed where microglia could be transiently depleted and replenished through a short-term administration of diphtheria toxin (DT).² Quantifying the number of newly generated immature neurons expressing microtubule-associated protein doublecortin (DCX) provided an assessment of hippocampal neurogenesis.² IL-6 receptor blocking antibody MR16-1 was injected into the hippocampus to investigate the role of IL-6 in neurogenesis.² Injection of soluble gp130-Fc, a protein that only blocks IL-6 trans-signaling, was also administered into the hippocampus to ascertain if IL-6 signaling worked through the classic or trans-signaling pathway.² Results: Depletion of microglia via PLX5622-containing diet did not improve the cognitive performance of TBI mice.² However, spontaneous repopulation of microglia following their depletion alleviated learning deficits in the APA task.² The number of DCX+ newly born neurons increased by ∼2-fold in CX₃CR1cre^ERT2 x iDTR mice receiving DT after TBI.² Blockade of IL-6 receptor led to the loss of cognitive and neurogenic benefits associated with microglial turnover and administration of MR16-1 reduced microglial proliferation.² sgp130-Fc injection also blocked the behavioral and neurogenic benefits related to the repopulating microglia.² Improvements in TBI outcomes mediated by repopulating microglia after TBI were also abolished when IL-6 trans-signaling was blocked.²  Conclusion: Depletion of activated microglia in regions affected by injury has little effect on TBI outcomes. However, microglial cells that repopulate after removing activated microglia enhance hippocampal neurogenesis, leading to improved cognitive function. IL-6 trans-signaling plays a key role in mediating the beneficial effects of repopulated microglia on hippocampal neurogenesis and cognitive function. Future studies could focus on further elucidating this mechanism to be taken advantage of therapeutically.

1. Maas AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. Dec 2017;16(12):987-1048. doi:10.1016/s1474-4422(17)30371-x
2. Willis EF, MacDonald KPA, Nguyen QH, et al. Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner. Cell. Mar 5 2020;180(5):833-846 e16. doi:10.1016/j.cell.2020.02.013
3. Scott G, Zetterberg H, Jolly A, et al. Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. Brain. Feb 1 2018;141(2):459-471. doi:10.1093/brain/awx339
4. Rice RA, Pham J, Lee RJ, Najafi AR, West BL, Green KN. Microglial repopulation resolves inflammation and promotes brain recovery after injury. Glia. Jun 2017;65(6):931-944. doi:10.1002/glia.23135
5. Elmore MRP, Hohsfield LA, Kramár EA, et al. Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice. Aging Cell. Dec 2018;17(6):e12832. doi:10.1111/acel.12832
6. 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. The Journal of Neuroscience. 2020;40(14):2960-2974. doi:10.1523/jneurosci.2402-19.2020