Role of damage-associated molecular patterns in the pathogenesis and therapeutics of traumatic brain injury

Abstract Traumatic brain injury (TBI) is a serious condition that poses a significant threat to human health globally. It is typically caused by direct trauma to the brain due to external forces such as impact or compression. The progression of TBI occurs in two stages based on physiological and pathological changes: primary and secondary brain injury. During the secondary stage, a large number of damage-associated molecular patterns (DAMPs) are released from injured cells into the extracellular space. These DAMPs trigger or exacerbate pathological conditions, including neuroinflammation, brain edema, diffuse axonal injury, and programmed cell death. The three main types of neural cells—neurons, microglia, and astrocytes—facilitate intercellular communication and functional crosstalk through the release and transmission of DAMPs. This forms the cellular foundation of secondary brain injury pathology. In the later stages of TBI, DAMPs are transported to various organs throughout the body via extracellular vesicles, leading to systemic changes and secondary injuries. Recent research has increasingly recognized the correlation between TBI and specific DAMPs. However, there remains a lack of comprehensive reviews exploring this relationship from a broader perspective. This review summarizes the primary pathological changes that occur after TBI, the types of DAMPs and their related signaling pathways, the role of DAMPs in mediating intercellular communication and neuronal crosstalk, and the relationship between DAMPs and systemic changes following TBI. This study also highlights that DAMPs represent promising targets for clinical diagnosis and treatment, which emphasizes the critical role of DAMPs in TBI.