Introduction

Psychological trauma is a pervasive risk factor for psychiatric and somatic disorders. However, the biological mechanisms that shape divergent outcomes remain incompletely understood [1]. Although many individuals recover following adversity, some develop chronic conditions such as posttraumatic stress disorder (PTSD), depression, or somatic syndromes characterized by fatigue and immune dysregulation. Traditional models emphasize hypothalamic–pituitary–adrenal (HPA) axis dysregulation, autonomic imbalance, and psychosocial context [2-4]. However, these frameworks do not fully explain why trauma of similar intensities can yield such heterogeneous trajectories. This review proposes a mechanistic hypothesis: that mitochondrial stress and adenosine triphosphate (ATP) signaling contribute to sustained neuroimmune activation in a subset of trauma responses. This ATP-linked cascade is presented not as a universal model, but as a conceptual framework describing one possible mechanistic pathway within a broader continuum of trauma responses. This framework complements existing models of trauma biology, including HPA-axis dysregulation, glucocorticoid resistance, and epigenetic remodeling, by offering a receptor-to-inflammasome perspective on trauma chronicity.

Elevated levels of inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP), have been consistently observed in trauma survivors and individuals with PTSD [5-7]. Inflammation has also been implicated in depression, fatigue, and cognitive impairment, suggesting a shared biological substrate across trauma-linked disorders [8].

Existing trauma-biology models emphasize HPA-axis dysregulation, glucocorticoid resistance, autonomic imbalance, and cytokine-based inflammation. Although these frameworks explain the broad patterns of stress reactivity, they offer limited specificity at the receptor level. The ATP-linked hypothesis proposed here differs in that it focuses on a defined biochemical cascade, mitochondrial stress, extracellular ATP efflux, P2X7 activation, NLRP3 assembly, and cGAS– STING amplification. This perspective provides additional explanatory power for the chronicity and developmental sensitivity of trauma responses.

Mitochondrial dysfunction can lead to the release of ATP into the extracellular space, where it acts as a danger-associated molecular pattern (DAMP) [9,10]. As extracellular ATP release is a core component of the cellular stress response, this cascade integrates psychotrauma with established stress-biology pathways.

Extracellular ATP activates P2X7 receptors, triggering ion flux, pore formation, and assembly of the NLRP3 inflammasome, which drives caspase-1 activation and the release of IL-1β and IL-18 [11-13]. In parallel, mitochondrial DNA (mtDNA) leakage activates the cGAS–STING pathway, amplifying innate immune responses through type I interferons and NF-κB signaling [14].

Additional receptors broaden and sustain trauma-linked inflammation. Toll-like Receptors (TLRs), particularly TLR4, detect DAMPs such as High Mobility Group Box1 (HMGB1) and heat-shock proteins, whereas the receptor for advanced glycation end products (RAGE) binds HMGB1 and S100 proteins, reinforcing NF-κB activation and cytokine persistence [15-18]. Collectively, these receptors form a danger-sensing network that converges on the NLRP3 inflammasome to ensure that once mitochondrial distress is translated into ATP leakage, the inflammatory cascade is amplified.

Conceptual Definitions

To avoid terminological ambiguity, this review adopts the following distinctions:

• Trauma (general): Any overwhelming physical or psychological event that threatens survival or integrity and is associated with lasting biological or psychological consequences.

• Preverbal trauma (0~3 years): Trauma occurring before the acquisition of language, when experiences are encoded in implicit, somatic, and sensory memory systems rather than explicit recall. Such trauma may be physical (e.g., neglect, abuse, and painful medical procedures) or relational/psychological (e.g., inconsistent caregiving). Owing to immature antioxidant defenses and heightened glial plasticity, the infant brain is disproportionately vulnerable to long-term neuroimmune priming.

• Resolving trauma subtype: Trauma that engages stress physiology in a reversible manner, without sustained neuroimmune activation. This term does not imply that such responses are trivial or psychological.

• ATP-linked trauma (hypothetical subtype): A proposed trauma subtype in which mitochondrial stress may lead to extracellular ATP efflux, P2X7 activation, and NLRP3 assembly. However, this conceptual model requires empirical validation.

• Conceptual note: These categories are heuristic distinctions rather than strict binaries. Trauma responses likely exist along a continuum of neuroimmune activation, shaped by developmental timing, mitochondrial resilience, and parallel mechanisms such as glucocorticoid resistance, HPA-axis dynamics, and epigenetic remodeling.

Preverbal Trauma and Implicit Memory

Trauma occurring during the preverbal period (0~3 years) represents a distinct vulnerability category. During this developmental window, infants lack language and encode experiences in implicit memory systems - somatic, sensory, and emotional-rather than explicit verbal recall [19,20]. Consequently, many adults may carry the imprint of preverbal trauma without conscious awareness of the original event.

Implicit memory involves the amygdala, brainstem, and sensory circuits that regulate autonomic and immune tones. Early stress can modify these circuits through epigenetic changes and altered microglial set-points, creating a form of neuroimmune priming. This provides a biological bridge between implicit memory and increased inflammatory reactivity later in life.

In this age group, verbal input is processed primarily through prosody, tone, and autonomic arousal rather than through semantic content. Thus, verbal abuse can exert physiological and emotional effects despite limited language comprehension, but its encoding occurs through non-linguistic pathways. Painful medical procedures, neglect, inconsistent caregiving, and exposure to violence are experienced through the body and nervous system and not through words. These exposures can prime the glial and immune pathways, creating latent susceptibility to heightened inflammatory reactivity in adulthood [21,22]. Developmental timing also modulates vulnerability. Early-life adversity has been shown to prime glial and immune pathways, creating a latent susceptibility to reactivation in adulthood [23]. During the preverbal period, immature antioxidant defenses and heightened glial plasticity may render the brain disproportionately sensitive to ATP efflux and its downstream effects. These insights suggest that trauma outcomes are shaped by the psychosocial context and biochemical factors that may influence whether stress physiology resolves or contributes to more persistent neuroimmune activation.

These developmental considerations suggest that early adversity may shape long-term patterns of neuroimmune sensitivity. However, the specific pathways involved remain unclear. Although early adversity increases vulnerability to neuroimmune sensitization, the outcomes remain heterogeneous, and the ATP-linked pathway described here is intended to characterize a subset of individuals who develop persistent trauma-related inflammation rather than the full spectrum of responses. Therefore, the ATP-linked cascade described in this review is presented as a hypothetical mechanistic pathway that may intersect with, but does not replace, established models of trauma biology, such as HPA-axis dysregulation, glucocorticoid resistance, and epigenetic remodeling.

Methodology

1. Search strategy

A structured literature search was conducted across PubMed, Scopus, and Web of Science databases. The following search terms were used to combine trauma-related concepts with molecular and immunological pathways using Boolean operators:

• (“psychological trauma” OR “early life stress” OR “childhood adversity” OR “PTSD”) AND

• (“mitochondria” OR “ATP” OR “P2X7” OR “NLRP3” OR “STING” OR “TLR4” OR “RAGE” OR “neuroinflammation”).

Reference lists of relevant reviews and primary studies were screened to identify additional sources [11,12,15].

This search strategy was intentionally mechanistic, focusing on receptor-level and mitochondrial pathways rather than on the broader correlational trauma literature. The final search was conducted on January 2, 2025, and no additional eligible studies were identified. The study selection process is summarized in Fig. 1.

2. Eligibility criteria

The inclusion criteria for the studies were as follows: (1) examined trauma, stress, or adversity; (2) measured mitochondrial dysfunction, ATP signaling, P2X7 activation, NLRP3 inflammasome activity, cGAS–STING signaling, or TLR4/RAGE pathways; and (3) provided receptor-level or mechanistic details.

Full-text articles were excluded if they lacked mechanistic data (e.g., cytokine-only studies), focused exclusively on physical injury without a psychological or neuroimmune context, did not measure mitochondrial or ATP-related pathways, or were not peer-reviewed. Of the 130 full-text articles screened, 111 were excluded, resulting in 19 studies suitable for mechanistic synthesis. As the included studies varied widely in design, species, and measurement approaches, a formal risk-of-bias tool was not applied. Instead, the studies were qualitatively appraised based on mechanistic clarity, receptor-level specificity, and relevance to the proposed cascade.

3. Study selection

We screened the titles and abstracts for relevance. The full texts of the potentially eligible studies were retrieved. Discrepancies were resolved through discussion and consensus.

4. Data extraction

The following data were extracted from each included study:

• Study type (clinical, preclinical, review).

• Trauma model or population studied.

• Molecular targets (mitochondria, ATP, P2X7, NLRP3, STING, TLR4 and RAGE).

• Key findings on neuroimmune signaling, cytokine release, or behavioral outcomes.

• Developmental timing (preverbal vs. later life).

To enhance reproducibility, data extraction followed a structured template that was applied consistently across all studies. The extracted variables included trauma model, mitochondrial or ATP-related measures, receptor pathways examined, and neuroimmune outcomes. Discrepancies were resolved through discussions.

Study selection and data extraction were conducted by a single reviewer using a structured and reproducible process. Titles and abstracts were screened for relevance to trauma and mechanistic pathways, followed by a full-text assessment of potentially eligible studies. Inclusion decisions were guided by predefined criteria focusing on mitochondrial dysfunction, extracellular ATP signaling, P2X7 activation, NLRP3 inflammasome activity, cGAS–STING signaling, and TLR4/RAGE pathways. Data were extracted using a standardized template that captured the trauma model or population, mitochondrial- or ATP-related measures, receptor-level targets, and neuroimmune outcomes. The extracted information was cross-checked for internal consistency, and the final synthesis reflected a coherent integration of the mechanistic findings across the included studies.

5. Synthesis approach

This review is best characterized as a narrative mechanistic synthesis rather than a full systematic review. Although a structured search and PRISMA diagram were used to enhance transparency, the primary aim was to integrate receptor-level and mitochondrial mechanisms rather than exhaustively summarizing all trauma-related literature. Given the heterogeneity of the study designs, a narrative synthesis was employed. The findings were organized into a cascade framework with sequential nodes:

1. Mitochondrial stress and ATP leakage.

2. P2X7 receptor activation and NLRP3 inflammasome assembly.

3. Amplification via cGAS–STING.

4. Persistence through TLR4 and RAGE.

5. Cytokine surge and neuroimmune remodeling.

6. Developmental modulation (preverbal trauma).

This framework was iteratively refined by cross-referencing mechanistic studies [11,13] with developmental and clinical literature [19,21,22].

6. Bias and limitations

• Publication bias was mitigated by including positive and negative findings where available.

• The cascade model integrates evidence across species and models; direct human molecular data remain limited.

• Preverbal trauma is under-studied at the molecular level, and extrapolations are cautiously drawn from developmental neuroscience and implicit memory research [20,23].

The search strategy prioritized receptor-level specificity (e.g., ATP, P2X7, NLRP3, STING, TLR4, and RAGE), which may have excluded broader neuroinflammatory studies that did not explicitly measure these pathways. Consequently, the evidence base is narrow, and the proposed cascade should be interpreted as a conceptual synthesis rather than a comprehensive account of all trauma-related biology. Future reviews incorporating cytokine-level, endocrine, and epigenetic studies may help contextualize this mechanistic hypothesis within a broader empirical landscape.

Results

1. Overview of included studies

Nineteen studies met the inclusion criteria and were synthesized into the proposed trauma cascade framework. These studies included clinical cohorts (n=7), preclinical animal models (n=8), and mechanistic in vitro investigations (n=4). Collectively, these studies examined trauma-linked mitochondrial dysfunction, ATP signaling, inflammasome activation, and downstream neuroimmune remodeling, with particular relevance for preverbal and adult contexts. The included studies exhibited substantial heterogeneity in trauma definitions and experimental paradigms. Preclinical models relied on physical stressors or maternal separation, whereas human studies examined psychological trauma and PTSD. These paradigms differ in intensity, chronicity, and ecological validity. Therefore, the integration presented here reflects mechanistic convergence rather than direct equivalence across the models.

The integration of these findings allowed the construction of a receptor-to-inflammasome cascade that explains how psychotrauma can transition from a reversible stress response to a chronic neuroinflammatory state. The proposed ATP-linked trauma cascade is illustrated in Fig. 2.

The mechanistic components of this cascade have been observed across species and experimental designs; however, the full sequence has not been directly demonstrated as a unified pathway. The integration presented here reflects a conceptual synthesis of convergent molecular findings rather than a fully validated cascade.

Table 1 provides a study-level summary of the 19 mechanistic studies included in the review, detailing the trauma or stress models, receptor-level targets, and key mechanistic findings.

1) Mitochondrial stress as the ignition point

Trauma exposure has been consistently associated with mitochondrial dysfunction in human and animal studies. While these findings apply broadly across trauma contexts, they are particularly relevant for preverbal trauma in which immature antioxidant defenses and heightened glial plasticity may amplify mitochondrial vulnerability. Preclinical models have demonstrated increased production of reactive oxygen species (ROS), altered mitochondrial membrane potential, and leakage of mitochondrial DNA into the cytosol [9,14]. These findings indicate that mitochondria are not passive victims of stress but are active participants in signaling danger to the immune system.

Clinical data reinforced this view. PTSD cohorts exhibited reduced mitochondrial resilience, impaired oxidative phosphorylation, and altered expression of mitochondrial genes [10]. Collectively, these findings support the interpretation that mitochondria may act as an early contributor to trauma associated biochemical signaling.

Biomarker/Therapeutic Implications: Circulating mtDNA fragments and mitochondrial copy number have been proposed as biomarkers of stress-related disorders [24]. Therapeutically, antioxidants and mitochondrial stabilizers such as coenzyme Q10 and mitophagy enhancers are being investigated for their effects on neuropsychiatric conditions [25].

2) ATP release and P2X7 receptor activation

The release of ATP into the extracellular space is one of the most prominent consequences of mitochondrial stress. Under normal conditions, ATP functions as an intracellular energy currency; however, when released at high concentrations, it acts as a DAMP. Preclinical studies have demonstrated that trauma-induced ATP-efflux reaching millimolar concentrations is sufficient to activate P2X7 receptors [11].

The activation of P2X7 receptors is consistent with that of ion flux, pore formation, and assembly of the NLRP3 inflammasome, leading to caspase-1 activation and the release of IL-1β and IL-18 [12,13]. Preclinical studies reporting millimolar ATP concentrations typically reflect localized microdomain spikes occurring at synapses or injury sites under controlled stimulation. Such concentrations are unlikely to occur uniformly in the human brain tissue. In vivo ATP levels are substantially lower, and translation from experimental conditions to human physiology requires caution. This limitation has been added to contextualize the mechanistic interpretation. Clinical studies support this mechanism, with trauma survivors exhibiting elevated plasma ATP levels. This receptor-level evidence positions ATP–P2X7 signaling as the biochemical ignition switch of trauma.

Biomarker/Therapeutic Implications: Plasma ATP has been suggested as a biomarker for systemic inflammation [26]. P2X7 antagonists such as Brilliant Blue G and experimental small molecules are being tested in neurodegeneration models and may be repurposed for trauma-related inflammation [27].

3) NLRP3 inflammasome assembly and cytokine release

The NLRP3 inflammasome has been consistently implicated as an execution hub for trauma-induced inflammation. Preclinical studies have demonstrated that its activation may contribute to the maturation and release of IL-1β and IL-18, amplifying microglial activation and synaptic remodeling. Chronic inflammasome activation has been linked to depressive-like behaviors and cognitive impairment in animal models.

The clinical evidence supports these findings. Elevated IL-1β has been observed in trauma survivors and is correlated with symptom severity [5,6]. These results suggest that NLRP3 activation is not a transient event but a sustained driver of neuroimmune pathology, bridging cellular stress with behavioral outcomes.

Biomarker/Therapeutic Implications: IL-1β and IL-18 are measurable in plasma and CSF and have been proposed as biomarkers of inflammasome activity [28]. NLRP3 inhibitors, such as MCC950, have shown efficacy in preclinical models of neuroinflammation [29].

4) Amplification via the cGAS–STING pathway

Psychological stress alters mitochondrial dynamics through glucocorticoid signaling, oxidative load, and impaired mitophagy. These processes increase the likelihood of mitochondrial membrane permeabilization and mtDNA leakage into the cytosol, activating cGAS. Subsequently, STING engagement amplifies inflammatory signaling through IRF3 and NF-κB pathways. Although direct human evidence is limited, this sequence is well supported in preclinical stress models. Mitochondrial DNA leakage into the cytosol activates the cGAS–STING pathway, prolonging inflammatory signaling through type I interferons and NF-κB [14]. This amplification loop has been observed in trauma-exposed rodents and in vitro models of mitochondrial stress, indicating that — cGAS–STING is a conserved mechanism of trauma-induced inflammation.

The significance of this pathway lies in its ability to extend the inflammatory response beyond the initial ATP–P2X7–NLRP3 activation. By sustaining interferon and NF-κB signaling, cGAS– STING ensures that trauma-induced inflammation persists long after the original stressor has passed, contributing to the chronicity of trauma outcomes.

Biomarker/Therapeutic Implications: Interferon-stimulated gene signatures in peripheral blood have been proposed as biomarkers of cGAS –STING activation [30]. STING modulators, which are currently in oncology pipelines, are being explored to treat autoimmune and inflammatory diseases [31].

5) Persistence through TLR4 and RAGE

Danger-associated molecules such as the HMGB1 and S100 proteins activate TLR4 and RAGE, reinforcing NF-κB signaling and sustaining cytokine output [15-18]. These receptors act as persistence nodes—once the cascade is triggered, it does not readily resolve.

Evidence from traumatic brain injury models has confirmed that HMGB1–RAGE signaling exacerbates neuroinflammation and worsens outcomes. Clinical studies have reported elevated HMGB1 levels in trauma survivors, linking this pathway to persistent inflammation. Thus, TLR4 and RAGE provide a molecular basis for the non-resolution of trauma-induced inflammation.

Biomarker/Therapeutic Implications: HMGB1 is measurable in serum and CSF and has been proposed as a biomarker of persistent inflammation [15]. Therapeutically, TLR4 antagonists (e.g., TAK-242) and RAGE inhibitors are being investigated for sepsis and neurodegeneration [32].

6) Cytokine surge and neuroimmune remodeling

The combined activation of P2X7, NLRP3, STING, TLR4, and RAGE produced a cytokine surge dominated by IL-1β, TNF-α, and IL-6. These cytokines drive microglial reactivity, astrocytic activation, and synaptic pruning, leading to circuit remodeling and neurodegeneration [7].

Clinical studies have linked elevated levels of inflammatory markers to PTSD severity and comorbid depression [5]. This convergence of preclinical and clinical evidence underscores the translational importance of the cytokine surge, positioning it as the final common pathway through which trauma reshapes neural circuits and behavior.

Biomarker/Therapeutic Implications: IL-6 and TNF-α are widely used as clinical biomarkers of systemic inflammation [33]. Anti-cytokine therapies, such as anakinra (IL-1 receptor antagonist) and infliximab (a TNF-α inhibitor), have shown promise in treating inflammatory disorders and may be repurposed for trauma-related pathology [34].

The receptor pathways implicated across the included studies are summarized in Table 2.

7) Developmental modulation: preverbal trauma

A subset of studies emphasized the role of developmental timing. Trauma occurring in the preverbal period (0~3 years) is associated with long-lasting priming of the glial and immune pathways [19,21,22]. The 0~3 year window corresponds to a period of rapid synaptogenesis, peak glial plasticity, immature antioxidant systems, and accelerated myelination. These developmental features increase the vulnerability to oxidative stress and may increase sensitivity to ATP-linked inflammatory cascades. This biological rationale supports the use of 0~3 years of age as a meaningful developmental boundary.

Adults with preverbal trauma typically lack explicit memory of events [20] but display heightened inflammatory reactivity. Thus, preverbal trauma survivors represent a biologically sensitized but clinically under-recognized population, highlighting the need for developmental considerations in trauma research and clinical practice.

Biomarker/Therapeutic Implications: Epigenetic signatures such as the altered methylation of NR3C1 and FKBP5 have been linked to early adversity and may serve as biomarkers of preverbal trauma [35]. Early interventions targeting mitochondrial resilience and glial priming may reduce long-term vulnerability.

8) Distinguishing trauma responses along a neuroimmune continuum

The findings of this review suggest that trauma responses may vary along a continuum of neuroimmune activation rather than forming a strict binary. Some trauma exposures appear to engage in stress physiology reversibly, whereas others may lead to more sustained inflammatory signaling. The ATP-linked cascade described in this review represents a hypothetical mechanistic subtype within this broader continuum.

This subtype is characterized by mitochondrial stress, extracellular ATP efflux, P2X7 receptor activation, and NLRP3 inflammasome assembly. Nevertheless, current evidence does not allow definitive classification of individuals or trauma histories into discrete categories.

Therefore, the available evidence supports a conceptual model in which ATP-mediated neuroinflammation is a possible pathway contributing to trauma chronicity, rather than a universal or exclusive mechanism. Further research using stratified biomarkers and longitudinal designs is required to determine the clinical relevance and boundaries of the proposed subtypes.

Biomarker/Therapeutic Implications: Composite biomarker panels combining mtDNA, extracellular ATP, IL-1β, and HMGB1 may help identify individuals who exhibit stronger neuroimmune activation following trauma [8]. These patterns may have therapeutic implications, because individuals with stronger neuroimmune activation may benefit from targeted anti-inflammatory or mitochondrial interventions.

Discussion

1. Reframing trauma as a biochemical cascade

This review advances the reframing of psychotrauma from a primarily psychosocial construct to a mechanistic hypothesis in which trauma may engage a sustained neuroimmune cascade under certain conditions. Trauma responses likely vary along a continuum of neuroimmune activation. Some exposures may be resolved through reversible stress physiology, whereas others may engage in more persistent inflammatory signaling. The ATP-linked cascade described in this review represents a hypothetical pathway within this broader continuum. Traditional models have emphasized dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, alterations in autonomic tone, and the role of cognitive appraisal in shaping outcomes [1,3]. Although these frameworks remain valuable, they do not fully explain why trauma of similar intensity can yield divergent trajectories across individuals.

The concept of a “threshold” between reversible stress physiology and more persistent neuroinflammation is presented as a heuristic rather than a fixed biological boundary. This threshold reflects the interaction between mitochondrial resilience, reactive oxygen species load, developmental timing, and parallel mechanisms, such as glucocorticoid resistance. Current evidence does not support a discrete cutoff; instead, these factors likely shift individuals along a continuum of neuroimmune activation.

The cascade model proposed here integrates mitochondrial biology, purinergic signaling, inflammasome activation, and developmental neuroscience into a unified framework. Extracellular ATP release and NLRP3 activation are not specific to psychological trauma, but they occur during infection, autoimmunity, metabolic stress, and TBI. The relevance of these pathways to psychotrauma lies not in their specificity but in their potential to act as convergence points where psychological stress interfaces with mitochondrial and immune signaling. Therefore, this model proposes a plausible mechanistic route rather than a trauma-exclusive pathway. By situating trauma within the context of danger-associated molecular patterns (DAMPs) and receptor-mediated amplification loops, this model illustrates how mitochondrial stress contributes to sustained neuroimmune activation in some trauma contexts. This conceptual shift has implications for mechanistic understanding, clinical classification, biomarker development, and therapeutic targeting.

Mitochondrial resilience, developmental timing, metabolic context, and parallel mechanisms such as glucocorticoid resistance and epigenetic remodeling, likely interact to shape individual trajectories. Therefore, the concept of a mitochondrial “threshold” is presented as a heuristic rather than a validated biological boundary.

2. Amplification and persistence mechanisms

Psychological stress alters mitochondrial dynamics through glucocorticoid signaling, oxidative load, and impaired mitophagy. These processes increase the likelihood of mitochondrial membrane permeabilization and mtDNA leakage into the cytosol, activating cGAS. Subsequently, STING engagement amplifies inflammatory signaling through IRF3 and NF-κB pathways. Although direct human evidence is limited, this sequence is well-supported in preclinical stress models.

The cascade model emphasizes that, once initiated, trauma-induced inflammation is amplified and sustained by multiple receptor systems.

• cGAS–STING pathway: Activated by mitochondrial DNA leakage, this pathway prolongs inflammation through type I interferons and NF-κB signaling [14].

• TLR4 and RAGE: Activated by the HMGB1 and S100 proteins, these receptors reinforce NF-κ B activity and sustain cytokine output [15,18].

These pathways are not unique to trauma and may interact with broader stress-biology systems, including the HPA-axis dynamics and glucocorticoid signaling. These amplification loops explain the chronicity of trauma outcomes. Even after the original stressor has passed, the molecular cascade continues to drive neuroimmune remodeling. This persistence may underlie the relapsing course of PTSD, depression, and trauma-linked somatic syndrome.

Although extracellular ATP release, P2X7 activation, and NLRP3 inflammasome assembly occur in many inflammatory conditions, their relevance to psychological trauma lies in their potential to act as convergence points where stress-related mitochondrial dysfunction interfaces with immune signaling. Therefore, the model proposes a plausible mechanistic route for a subset of trauma responses rather than a trauma-specific or exclusive pathway.

3. Cytokine surge and neuroimmune remodeling

The downstream consequence of this cascade is a cytokine surge dominated by IL-1β, TNF-α, and IL-6. These cytokines drive microglial reactivity, astrocytic activation, and synaptic pruning, leading to long-term changes in neural circuitry [5,7]. Such remodeling may explain the enduring alterations in fear processing, memory consolidation, and affect regulation observed in trauma survivors.

Importantly, cytokine-linked remodeling is not limited to the brain. Peripheral inflammation contributes to fatigue, metabolic dysregulation, and increased risk of cardiovascular disease in trauma-exposed populations. Thus, the cascade model provides a unifying explanation for the psychiatric and somatic comorbidities associated with trauma. Nevertheless, the current evidence does not allow the attribution of specific symptom clusters to any single mechanistic pathway.

4. Developmental timing and preverbal trauma

One of the most novel aspects of this model is its integration of developmental timing. Trauma occurring in the preverbal period (0~3 years) is encoded in implicit memory systems rather than explicit recall [19,20]. During this window, immature antioxidant defenses and heightened glial plasticity render the brain disproportionately sensitive to ATP efflux and inflammasome activation [21,22].

Therefore, adults with preverbal trauma may carry biological imprints of trauma without conscious memory. This group is often under-recognized in clinical practice, but may exhibit heightened inflammatory reactivity throughout the lifespan. Recognizing preverbal trauma as a biological risk factor may improve screening and intervention strategies, particularly for populations with unexplained inflammatory or psychiatric symptoms.

5. Translational implications

The cascade model highlights several therapeutic targets:

• P2X7 antagonists (e.g., Brilliant Blue G, experimental small molecules) to block ATP-linked inflammasome activation.

• NLRP3 inhibitors (e.g., MCC950) to prevent cytokine maturation.

• STING modulators to dampen persistent interferon signaling.

• TLR4 and RAGE blockers to disrupt HMGB1-mediated persistence.

• Mitochondrial stabilizers (antioxidants, mitophagy enhancers) to prevent the initial ignition.

Translational opportunities across mechanistic nodes are summarized in Table 3.

If validated in trauma populations, these interventions could shift treatment paradigms from symptom suppression to mechanism-based prevention of neuroimmune remodeling. Moreover, the model suggests that biomarkers such as extracellular ATP, inflammasome components, or HMGB1 may help identify individuals who exhibit stronger neuroimmune activation following trauma.

6. Integration with existing models

The cascade model does not replace but complements existing frameworks. Dysregulation of the HPA axis, autonomic imbalance, and the psychosocial context remain critical determinants of psychotraumatic outcomes. However, by adding a molecular layer, this model provides a mechanistic bridge between psychological stress and mitochondrial-linked pathology.

Ultimately, this framework offers a conceptual pathway that may help refine the understanding and investigation of trauma, providing a bridge between molecular mechanisms and clinical observations while acknowledging that further empirical work is necessary before clinical translation.

Clinically, this hypothesis may help identify trauma subtypes characterized by stronger neuroimmune activation, guide biomarker-based stratification, and inform mechanism-based interventions. By offering receptor-level specificity, the model may clarify why individuals with similar trauma exposures exhibit divergent trajectories.

As the included studies are cross-sectional or preclinical, causal inferences were limited. Therefore, the proposed cascade should be interpreted as a conceptual synthesis rather than evidence of a direct causal pathway. Longitudinal and experimental studies are necessary to clarify the temporal relationships.

The mechanistic pathways described in this review are drawn heavily from preclinical models, in vitro inflammasome studies, and trauma paradigms that do not fully replicate human psychological trauma. Consequently, the proposed ATP-linked cascade cannot be interpreted as a validated causal pathway. Instead, it represents a conceptual integration of convergent molecular findings. Direct human evidence for ATP efflux, P2X7 activation, or cGAS–STING signaling following psychological trauma remains limited, and longitudinal studies are necessary to determine temporal ordering and causal relevance.

7. Limitations

Several limitations of this review must be acknowledged. First, much of the mechanistic evidence underlying the proposed ATP-linked cascade has been derived from preclinical models (animal and in vitro studies). Although these models provide valuable insights into receptor-level and inflammasomes, their direct translation to human psychotrauma remains incomplete. Second, the role of developmental timing, particularly preverbal trauma, was inferred from indirect evidence obtained from developmental neuroscience and implicit memory research. Longitudinal human studies are required to clarify whether early adversity uniquely shapes mitochondrial and glial vulnerability. Third, the included studies were heterogeneous in design, population, and outcome measures, which limited the feasibility of quantitative synthesis and necessitated a narrative approach that may have introduced interpretive bias. Fourth, although the cascade integrates multiple receptor systems (P2X7, NLRP3, cGAS–STING, TLR4, and RAGE), the relative contribution of each pathway in vivo remains uncertain, and interactions with broader stress-biology mechanisms require further investigation. Animal stress paradigms have limited validity as models of human psychological trauma in humans. Maternal separation, restraint stress, and forced swim tests capture aspects of stress physiology but do not replicate the cognitive, relational, or sociocultural dimensions of human trauma. These limitations constrain the generalizability of the mechanistic findings. Finally, publication bias cannot be excluded, as negative or null findings are less likely to be reported, potentially inflating the apparent strength of the associations.

Despite these limitations, this synthesis offers a conceptually novel framework linking mitochondrial stress, ATP signaling, and neuroimmune remodeling within a continuum model of trauma responses. Future research should prioritize biomarker validation, longitudinal developmental studies, and clinical trials of targeted interventions to test and refine this hypothesis.

8. Future directions

Future research should focus on the following:

• Identifying biomarkers of ATP-linked trauma (e.g., extracellular ATP, inflammasome components, and HMGB1).

• Testing targeted interventions in trauma-exposed populations.

• Exploring gene–environment interactions that modulate mitochondrial thresholds.

• Developing longitudinal cohorts to track the impact of preverbal trauma across the lifespan.

• Conducting systems biology and computational modeling to simulate cascade dynamics and predict intervention points.

Conclusion

This review advances a conceptual framework for understanding psychotrauma that incorporates mitochondrial stress, ATP signaling, inflammasome activation, and developmental vulnerability into a unified neuroimmune perspective. Rather than positioning trauma as a biochemical ignition event or implying a discrete threshold, the model proposes that mitochondrial stress and extracellular ATP release contribute to persistent neuroimmune activation under certain conditions. This hypothesis offers a mechanistic pathway that may help explain the heterogeneity of trauma outcomes and complement the existing psychological, social, and endocrine models.

Within this framework, ATP-linked neuroimmune activation represents a hypothetical pathway that may emerge in the contexts of increased mitochondrial vulnerability, including early adversity. Trauma occurring in the first three years of life is encoded in implicit memory systems and may shape long-term neuroimmune sensitivity through immature antioxidant defenses and heightened glial plasticity. Therefore, adults with preverbal trauma may exhibit increased inflammatory reactivity despite lacking explicit memory of early events, underscoring the importance of developmental timing in trauma research and clinical assessment.

The proposed cascade highlights several potential therapeutic targets, including P2X7 receptors, the NLRP3 inflammasome, cGAS–STING signaling, and TLR4/RAGE pathways, as well as mitochondrial stabilizing strategies. Biomarkers such as extracellular ATP, inflammasome components, and HMGB1 may eventually support stratified research designs aimed at identifying individuals who exhibit stronger neuroimmune activation after trauma. These possibilities remain exploratory but point toward future mechanism-informed interventions.

Importantly, this framework does not replace established models of psychotrauma. HPA-axis dynamics, autonomic regulation, cognitive appraisal, and psychosocial context remain the central determinants of outcomes. The ATP-linked cascade adds a molecular layer that may help bridge psychological stress through neuroimmune remodeling, aligning with the growing recognition that trauma involves interconnected biological and experiential processes.

Despite being supported by convergent preclinical and clinical findings, the proposed model remains a mechanistic hypothesis. Direct human evidence is limited, and the relative contribution of each pathway in vivo is not yet known. Future research should prioritize longitudinal cohorts, biomarker validation, developmental studies, and targeted clinical trials. Systems biology and computational modeling may further clarify pathway interactions and identify optimal intervention points.

In summary, this review offers a conceptual pathway that integrates mitochondrial stress, ATP signaling, and developmental vulnerability into a broader psychoneuroimmunological understanding of trauma. By situating ATP-linked neuroimmune activation within a continuum of trauma responses, the model provides a foundation for future empirical testing while avoiding categorical distinctions or premature clinical application.

Notes

Conflicts of interest

The author declared no conflict of interest.

Funding

None.

Fig. 1.

PRISMA flow diagram summarizing the identification, screening, eligibility assessment, and inclusion of studies. A total of 1,282 records were identified, 130 full text articles were assessed for eligibility, and 19 studies met the criteria for inclusion in the mechanistic synthesis.

Fig. 2.

ATP–inflammasome neuroimmune trauma cascade. Psychological trauma may initiate mitochondrial stress responses that are typically reversible but can progress to extracellular ATP efflux, P2X7 receptor activation, and NLRP3 inflammasome assembly under conditions of heightened mitochondrial vulnerability. The cascade can amplify through cGAS–STING signaling and persist via TLR4 and RAGE engagement, leading to cytokine surges (IL-1β, IL-6, TNF-α, IL-18) and long-term neuroimmune remodeling. Preverbal trauma is depicted as one developmental context that may increase sensitivity to these pathways, illustrating a potential trajectory within a broader continuum of trauma responses rather than a discrete category.

References

• 1. Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007;56:19-32. https://doi.org/10.1016/j.neuron.2007.09.006ArticlePubMed
• 2. McEwen BS. Neurobiological and systemic effects of chronic stress. Nat Neurosci. 2017;20:242-249. https://doi.org/10.1177/2470547017692328ArticlePubMedPMC
• 3. Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB. Altered pituitary adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry. 2001;158:575-582. https://doi.org/10.1176/appi.ajp.158.4.575ArticlePubMed
• 4. Southwick SM, Vythilingam M, Charney DS. The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol. 2005;1:255-291. https://doi.org/10.1146/annurev.clinpsy.1.102803.143948ArticlePubMed
• 5. Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T. Inflammation in fearand anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacology. 2017;42:254-270. https://doi.org/10.1038/npp.2016.146ArticlePubMedPMC
• 6. Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2:1002-1012. https://doi.org/10.1016/S2215-0366(15)00309-0ArticlePubMed
• 7. Speer K, Upton D, Semple S, McKune A. Systemic low-grade inflammation in post-traumatic stress disorder: a systematic review. J Inflamm Res. 2018;11:111-121. https://doi.org/10.2147/JIR.S155903ArticlePubMedPMC
• 8. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22-34. https://doi.org/10.1038/nri.2015.5ArticlePubMedPMC
• 9. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221-225. https://doi.org/10.1038/nature09663ArticlePubMed
• 10. Pei L, Wallace DC. Mitochondrial etiology of neuropsychiatric disorders. Biol Psychiatry. 2018;83:722-730. https://doi.org/10.1016/j.biopsych.2017.11.018ArticlePubMedPMC
• 11. Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. The P2X7 receptor in infection and inflammation. Immunity. 2017;47:15-31. https://doi.org/10.1016/j.immuni.2017.06.020ArticlePubMedPMC
• 12. Cai X, Yao Y, Teng F, Li Y, Wu L, Yan W, Lin N. The role of P2X7 receptor in infection and metabolism: Based on inflammation and immunity. Int Immunopharmacol. 2021;101:108297. https://doi.org/10.1016/j.intimp.2021.108297ArticlePubMed
• 13. Faas MM, Sáez T, de Vos P. Extracellular ATP and adenosine: the Yin and Yang in immune responses? Mol Aspects Med. 2017;55:9-19. https://doi.org/10.1016/j.mam.2017.01.002ArticlePubMed
• 14. West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520:553-557. https://doi.org/10.1038/nature14156ArticlePubMedPMC
• 15. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139-162. https://doi.org/10.1146/annurev-immunol-030409-101323ArticlePubMedPMC
• 16. Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure, functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013;93:865-873. https://doi.org/10.1189/jlb.1212662ArticlePubMedPMC
• 17. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005;5:331-342. https://doi.org/10.1038/nri1594ArticlePubMed
• 18. Paudel YN, Angelopoulou E, Piperi C, Othman I, Shaikh MF. HMGB1 mediated neuroinflammatory responses in brain injuries: potential mechanisms and therapeutic opportunities. Int J Mol Sci. 2020;21:4609. https://doi.org/10.3390/ijms21134609ArticlePubMedPMC
• 19. Schore AN. Affect regulation and the origin of the self: the neurobiology of emotional development. Hillsdale, NJ: Lawrence Erlbaum Associates; 2003.
• 20. Van der Kolk BA. The Body Keeps the Score: Brain, Mind, and Body in the Healing of Trauma. New York: Viking; 2014.
• 21. Teicher MH, Samson JA. Annual Research Review: enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatry. 2016;57:241-266. https://doi.org/10.1111/jcpp.12507ArticlePubMedPMC
• 22. Frank MG, Fonken LK, Watkins LR, Maier SF. Microglia: neuroimmune-sensors of stress. Semin Cell Dev Biol. 2019;94:176-185. https://doi.org/10.1016/j.semcdb.2019.01.001ArticlePubMedPMC
• 23. Danese A, Lewis SJ. Psychoneuroimmunology of early life stress: the hidden wounds of childhood trauma? Neuropsychopharmacology. 2017;42:99-114. https://doi.org/10.1038/npp.2016.198ArticlePubMedPMC
• 24. Picard M, McEwen BS. Psychological stress and mitochondria: a conceptual framework. Psychosom Med. 2018;80:126-140. https://doi.org/10.1097/PSY.0000000000000545ArticlePubMedPMC
• 25. Nicolson GL. Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Integr Med (Encinitas). 2014;13:35-43.
• 26. Cauwels A, Rogge E, Vandendriessche B, Shiva S, Brouckaert P. Extracellular ATP drives systemic inflammation, tissue damage, and mortality. Cell Death Dis. 2014;5:e1102. https://doi.org/10.1038/cddis.2014.70ArticlePubMedPMC
• 27. Bhattacharya A, Biber K. The microglial ATP gated ion channel P2X7 as a CNS drug target. Glia. 2016;64:1772-1787. https://doi.org/10.1002/glia.23001ArticlePubMed
• 28. Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018;19:610-621. https://doi.org/10.1038/s41583-018-0055-7ArticlePubMed
• 29. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21:248-255. https://doi.org/10.1038/nm.3806ArticlePubMedPMC
• 30. Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20:657-674. https://doi.org/10.1038/s41576-019-0151-1ArticlePubMedPMC
• 31. Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021;21:548-569. https://doi.org/10.1038/s41577-021-00524-zArticlePubMedPMC
• 32. Gao TL, Yuan XT, Yang D, Dai HL, Wang WJ, Peng X, Shao HJ, Jin ZF, Fu ZJ. Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury. J Trauma Acute Care Surg. 2012;72:102-109. https://doi:10.1097/TA.0b013e31823c54a6
• 33. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46-56. https://doi.org/10.1038/nrn2297ArticlePubMedPMC
• 34. Khandaker GM, Dantzer R, Jones PB. Immunopsychiatry: important facts. Psychol Med. 2017;47:2229-2237. https://doi.org/10.1017/S0033291717000745ArticlePubMedPMC
• 35. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16:33-41. https://doi.org/10.1038/nn.3275ArticlePubMedPMC

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