Summary: After traumatic brain injury (TBI), the brain’s immune cells show a marked slowdown in their internal recycling process (autophagy), allowing cellular waste to accumulate and worsen inflammation and recovery. Stimulating autophagy with rapamycin reduced neuroinflammation and improved functional recovery in a mouse model of TBI.
Source: University of Maryland
Every year in the United States, roughly 1.5 million people survive a traumatic brain injury caused by falls, motor vehicle collisions, sports incidents, or other blunt trauma. Such injuries can produce immediate damage and long-term disability, making improved treatments a major medical priority.
Researchers at the University of Maryland School of Medicine (UMSOM) studied how different brain cell types respond to severe trauma in a controlled mouse model of TBI. Their work focused on autophagy, the cellular process that removes and recycles damaged or worn-out components. Impaired autophagy can allow toxic material to accumulate and aggravate injury.
Published in the January issue of Autophagy, the new study reports that autophagy becomes significantly suppressed not only in neurons but also in the brain’s immune cells—microglia and infiltrating macrophages—after TBI. This suppression reduces the cells’ ability to clear debris and inflammatory signals, amplifying neuroinflammation and impairing recovery.
The investigators found that mice with experimentally induced TBI showed a notable decline in autophagy within microglia and macrophages. When the team genetically removed a key autophagy gene (Becn1) specifically from these immune cells, TBI-induced inflammation intensified: innate immune pathways such as type I interferon signaling and inflammasome activation were excessive, and phagocytic clearance of danger signals declined. These changes led to more neurodegeneration and worse cognitive outcomes in the long term.
Microglia are the brain’s resident immune cells and can perform extensive cleanup, engulfing and digesting damaged cells and debris. Following injury, peripheral white blood cells (macrophages) also cross the damaged blood–brain barrier and join microglia in clearing damage-associated molecular patterns (DAMPs). Efficient autophagy in these cells is therefore essential to resolve inflammation and support tissue repair.
To test whether boosting autophagy could improve outcomes after TBI, the team treated injured mice with rapamycin, a drug known to enhance autophagy by inhibiting mTOR signaling. Rapamycin-treated animals showed lower markers of neuroinflammation and improved performance on cognitive testing compared with untreated controls. Conversely, blocking autophagy in microglia and macrophages produced worse inflammation and cognitive decline than TBI alone.
Lead investigator Marta Lipinski, PhD, Associate Professor of Anesthesiology and Anatomy & Neurobiology at UMSOM, emphasized the translational potential of these findings: promoting autophagy in immune cells of the injured brain could be a promising strategy to limit secondary damage after TBI. However, rapamycin itself affects multiple cellular pathways involved in regeneration and cannot be used long term without risk. The team therefore highlights the need to identify more selective approaches that enhance protective autophagy in immune cells without disrupting essential regenerative processes.
Dean Mark Gladwin, MD, noted that effective TBI therapies will require a precise understanding of interactions among neurons, microglia, and infiltrating immune cells, since each cell type contributes differently to inflammation and healing. The current study provides important mechanistic insight into how impaired autophagy in immune cells magnifies innate immune responses and obstructs recovery.
Funding: This research was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (R01NS094527, R01NS091218, R01NS115876).
About this TBI research news
Author: Vanessa McMains
Source: University of Maryland
Contact: Vanessa McMains – University of Maryland
Image: The image is in the public domain
Original Research: Open access. “Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes” by Marta Lipinski et al., published in Autophagy.
Abstract
Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes
Excessive and prolonged neuroinflammation after traumatic brain injury contributes to long-term tissue damage and poor functional recovery. The molecular drivers of exaggerated inflammatory responses following TBI are not fully understood.
Prior work showed that autophagy flux is inhibited in neurons after TBI in mice, contributing to neuronal death. The present study extends these findings to brain immune cells, demonstrating that activated microglia and infiltrating macrophages also show impaired autophagy after injury, which potentiates neuroinflammatory signaling.
Conditional knockout of the essential autophagy gene Becn1 in macrophages and microglia increased neuroinflammation and heightened activation of innate immune pathways, including type I interferon responses and inflammasome signaling. Impaired autophagy reduced phagocytic clearance of DAMPs that normally limit innate immune activation. The data also indicate a role for selective autophagy in targeting components of innate immune pathways, such as the NLRP3 inflammasome, for degradation.
Inhibition of microglial/macrophage autophagy increased neurodegeneration and produced worse long-term cognitive outcomes after TBI. Conversely, enhancing autophagy with rapamycin decreased inflammation and improved outcomes in wild-type mice. Overall, these results show that autophagy failure in brain immune cells contributes to excessive neuroinflammation after injury and may prevent resolution and tissue repair, identifying autophagy modulation as a potential therapeutic avenue for traumatic brain injury.