Traumatic brain injury (TBI) is a leading cause of neurological disorders and significantly contributes to global morbidity and mortality [1]. Each year, approximately 74 million individuals are affected by TBI, predominantly resulting from high-impact events such as vehicular accidents, sports injuries, and explosive blasts. The consequences of TBI can be profound, leading to physical and behavioral impairments that include partial paralysis, motor dysfunction, and long-term cognitive deficits. These impairments impose substantial socioeconomic burdens on both patients and their families [2]. Despite the devastating impact of TBI, there are currently no targeted therapies available; treatment primarily remains symptomatic, relying on interventions such as diuretics and antiseizure medications to manage acute clinical symptoms [3]. The pursuit of effective neuroprotective strategies has placed considerable emphasis on understanding the complex mechanisms underlying secondary injury processes that exacerbate brain damage following TBI [4]. Brain injury resulting from TBI can be classified into primary and secondary injuries. Primary injury encompasses the immediate mechanical trauma sustained during the event, which includes the disruption of the blood-brain barrier (BBB), endothelial damage, and white matter injury [5], [6], [7]. This initial trauma triggers a cascade of secondary injury processes that develop over hours to days, driven by intricate biochemical and cellular events that further exacerbate neuronal damage. These processes include microglial activation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and persistent neuroinflammation [8].

Among these processes, neuroinflammation has emerged as a critical yet poorly understood component of TBI pathology. This inflammatory response is characterized by the activation of resident immune cells, such as microglia and astrocytes, along with the infiltration of peripheral immune cells into the brain. A central element of the neuroinflammatory response in TBI is the activation of pattern recognition receptors (PRRs), which are crucial for sensing and responding to endogenous danger signals released from damaged brain cells. In the aftermath of TBI, damaged or necrotic cells release cellular debris that acts as damage-associated molecular patterns (DAMPs). These DAMPs are recognized by PRRs expressed on the surfaces of neighboring microglia and astrocytes, initiating a cascade of immune responses [9]. Upon activation, PRRs initiate signaling pathways that modulate the release of inflammatory mediators, such as cytokines, chemokines, and reactive oxygen species (ROS), which contribute to BBB disruption, neuronal death, and the recruitment of peripheral immune cells. The widespread presence of PRRs in the brain and the release of DAMPs in injured areas imply the significant involvement of these receptor families in orchestrating inflammation following TBI. Moreover, inhibiting these signaling pathways has shown promise in preventing synaptic loss and BBB damage, thereby expediting tissue repair [10], [11], [12], [13]. Consequently, therapeutic agents targeting PRRs may represent novel treatments for TBI. Despite the critical role of PRRs in regulating neuroinflammatory responses, the precise mechanisms by which these receptors contribute to TBI pathology remain incompletely understood. Emerging evidence highlights the complexity of PRR signaling networks and their diverse effects on immune cell activation, neurotoxicity, and tissue repair.

This review provides a comprehensive analysis of the mechanistic insights into PRR activation and signaling in TBI, emphasizing their role in neuroinflammation and injury progression. We explore the therapeutic potential of targeting PRRs and their downstream pathways, examining recent findings and evaluating strategies that may enhance TBI outcomes. By elucidating the multifaceted roles of PRRs in TBI, this review aims to identify new avenues for research and therapeutic intervention, ultimately striving to alleviate the long-term impact of this devastating injury.