Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge

Abstract

BackgroundNociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation.ResultsTo test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1–9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs).ConclusionsWe conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.

Skull Fractures Induce Neuroinflammation and Worsen Outcomes after Closed Head Injury in Mice

“…[17][18][19][20][21] Controlled cortical impact and fluid percussion injury models, procedures that need a craniotomy, induce comparable high cytokine expression. 12,[22][23][24] Because in a previous study we observed that approximately 30% of mice experienced skull fractures after WD injury (unpublished data), we hypothesize that injury to the skull may be one of the main triggers for the expression of inflammatory genes in the brain after WD injury and may thus contribute to the variability observed in this valuable TBI model. Therefore, the aim of the present study was to compare the inflammatory response after WD injury in the hippocampus and striatum of mice and correlate these findings with the presence and severity of skull fractures.…”

Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration

“…he peripheral nerves that communicate skin, muscle, and sensory organs with the brain must maintain functionality throughout life despite frequent stress and trauma [1][2][3][4][5][6] . Loss of integrity of peripheral neurons and associated cells, including glia, is a common occurrence in severe neurological dysfunctions that include weakness, pain, and loss of sensation 7 .…”

Mild Traumatic Brain Injury is Associated With Effect of Inflammation on Structural Changes of Default Mode Network in Those Developing Chronic Pain 

“…CCL2 is one of chemokines that increases rapidly after various forms of experimental mTBI (37,38), contributing to secondary brain damage through attracting monocytes to sites of injury and in ammation (39). Moreover, mTBIinduced disruption of the blood-brain barrier (BBB)(40) allows the passage of in ammatory cells out of the injured brain, and initiates to an elevated systemic immune response to the genesis of nociceptor hypersensitivity post-TBI (11). Of particular interest is the nding of macroscopic GM hypertrophy in the dPCC (a core region in the DMN), which is related to the arousal, self-reference and breadth of attention (41), can mediate the contribution of circulating in ammatory biomarker (i.e.…”

“…TBI can induce a multitude of in ammatory biomarkers perpetuating the secondary injury to the brain (7,8), which upregulates central nerve system (CNS) excitability contributing to the generation and persistent of concomitant headache (9)(10)(11). Multiple pain disorders have altered grey matter volume (GMV) within the pain matrix (12,13).…”