Challenging the Role of Adaptive Immunity in Neurotrauma: Rag1^−/− Mice Lacking Mature B and T Cells Do Not Show Neuroprotection after Closed Head Injury

Abstract

The role of adaptive immunity in contributing to post-traumatic neuroinflammation and neuropathology after head injury remains largely unexplored. The present study was designed to investigate the pathophysiological sequelae of closed head injury in Rag1 -/ -mice devoid of mature B and T lymphocytes. C57BL/6 wild-type and Rag1 -/ -mice were subjected to experimental closed head injury, using a standardized weight-drop device. Outcome parameters consisted of neurological scoring, quantification of blood-brain barrier (BBB) function, measurement of inflammatory markers and mediators of apoptosis in serum and brain tissue, and assessment of neuronal cell death, astrogliosis, and tissue destruction. There was no difference between wild-type and Rag1-/ -mice with regard to injury severity and neurological impairment for up to 7 days after head injury. The extent of BBB dysfunction was in a similar range for both groups. Quantification of complement activation fragments in serum revealed significantly attenuated C3a levels in Rag1 -/ -mice compared to wild-type animals. In contrast, the levels of pro-and anti-inflammatory cytokines and pro-apoptotic and anti-apoptotic mediators remained in a similar range for both groups, and the histological analysis of brain sections did not reveal a difference in reactive astrogliosis, tissue destruction, and neuronal cell death in Rag1 -/ -compared to wild-type mice. These findings suggest that adaptive immunity is not of crucial importance for initiating and sustaining the inflammatory neuropathology after closed head injury. The attenuated extent of post-traumatic complement activation seen in Rag1 -/ -mice implies a cross-talk between innate and adaptive immune responses, which requires further investigation in future studies.

Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury

“…Rag1−/− mice, which are devoid of mature lymphocytes, exhibited no differences in outcomes for up to one week after TBI (45). While questioning the role of adaptive immunity after TBI, T-lymphocytes comprise functionally diverse subsets that exert both protective and detrimental roles in the CNS (46–48).…”

Inflammation and Neuroprotection in Traumatic Brain Injury

“…45 After brain injury, activated T cells are recruited to sites of damage, 46 and ROS release may facilitate this recruitment by activating endothelial barriers. 47 To address the role of T cells in TBI, a previous study 48 examined the response to closed-skull head injury in RAG1 knockout mice that lack mature T and B cells. No difference in any pathologic or neurologic parameters was observed between wild-type and RAG1 -deficient mice for up to 1 week.…”

Emerging Roles for the Immune System in Traumatic Brain Injury

“…In a study by Weckbach et al, Rag1 −/− mice were used to investigate how the absence of B and T cells influences brain pathology and neurological impairment following weight drop-induced TBI (58). Surprisingly, lacking the adaptive arm of the immune system did not appreciably affect neurological outcome, BBB integrity, pro- or anti-apoptotic mediators, hippocampal architecture, or astroglial activation in these studies.…”