Traumatic brain injury triggers inflammatory processes that can persist long after the mechanical insult. This commentary examines the award-winning study by Kodali and colleagues, in which a single intranasal dose of human mesenchymal stromal cell-derived extracellular vesicles 90 min after controlled cortical impact suppressed NLRP3-p38/MAPK signalling and prevented chronic cognitive and affective dysfunction in mice. The study combines a clinically attractive administration route with durable functional effects, helping to explain its rapid influence. Translation will nevertheless depend on establishing human intranasal delivery, defining active cargo and mechanisms, and developing reproducible potency and release assays for a heterogeneous biological product. The work is important because it suggests that early modulation of post-traumatic inflammation may alter the long-term course of brain injury.

Serotonergic psychedelics are promising treatments for neuropsychiatric disorders, and their immunomodulatory effects may contribute to their clinical efficacy. However, we lack a systematic review and meta-analysis of these effects across in vitro, in vivo non-human, and human studies. We systematically searched PubMed, EMBASE, Web of Science, PsycINFO, LILACS and ClinicalTrials.gov for all studies, published from database inception through February 9th, 2026, examining changes in immune markers after serotonergic psychedelic exposure, and meta-analyzed eligible studies. Of 9,195 studies screened, 61 studies met eligibility criteria for systematic review including 24 in vitro studies, 30 non-human in vivo studies, and seven human studies including data from 10 separate human trials. Results of the systematic review indicated that most in vitro (19/24) and non-human in vivo (25/30) studies reported anti-inflammatory effects of psychedelics. Human results were mixed with anti-inflammatory effects observed in 3/10 trials. Results of the meta-analysis of 18 eligible in vivo murine studies showed a significant decrease in proinflammatory cytokines in inflammatory models (standardized mean difference (SMD = -1.23, 95% CI [-1.54, -0.92]), but no significant effects in healthy murines (SMD = -0.06, 95% CI [-0.54, 0.43]), following treatment with a serotonergic psychedelic. Four human studies were eligible for meta-analysis; however, the small number of studies resulted in imprecise estimates and limited interpretability. Thus, while serotonergic psychedelics reduce proinflammatory cytokines in preclinical models of increased baseline inflammation, limited human evidence precludes conclusions about their translational potential.

Sex differences in neuroimmune crosstalk have been identified in preclinical research, yet sex divergent immune pathways in people with chronic pain remain poorly understood. We previously identified ex vivo whole-blood stimulation of toll-like receptor-4 (TLR4), a highly conserved innate immune receptor, as a marker of nociplastic pain in female patients with urologic pain, but whether this occurs in males is unknown. Male (n=73) and female (n=135) patients with chronic urologic pain recruited from university-based tertiary urology clinics were compared on pain, urinary symptoms, and immune response to ex vivo TLR4 stimulation. Cross-sectional analyses demonstrated that female patients with widespread or comorbid pain exhibited heightened global TLR4 responses compared to female patients with pelvic-localized pain and male patients. Conversely, male patients with comorbid pain demonstrated downregulated regulatory TLR4 responses compared to male patients with pelvic-localized pain. These findings reveal distinct immunological phenotypes between male and female chronic pain patients based on pain distribution (pelvic-localized versus widespread/comorbid). This work provides foundational evidence for sex-specific immune mechanisms, with implications for the identification and treatment of nociplastic pain.

Astrocyte elevated gene-1 (AEG-1), also known as metadherin or LYRIC, is a well-established tumor necrosis factor-alpha inducible oncogene. AEG-1 mRNA is ubiquitously expressed in all normal tissues, and at high levels in myeloid lineage cells. As a relatively novel scaffolding protein, the full spectrum of physiological functions involving AEG-1 is still not well known. AEG-1 protein regulates inflammation through its direct interaction with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a key regulator of pro-inflammatory cytokines (PICs). Using both global (AEG-1 KO) and myeloid-specific knockout (AEG-1[ΔMAC]) transgenic mouse strains, we aimed to determine whether AEG-1 influences the development of pain-like behaviors and neuroinflammation in a mouse model of complete Freund's adjuvant (CFA)-induced inflammatory pain. We hypothesized that deletion of AEG1 expression in myeloid cells, such as monocytes and macrophages, would prevent the initiation of chronic pain and associated neuroinflammation. The results showed that CFA-induced mechanical and thermal hypersensitivity were reduced in both AEG-1 KO and AEG-1[ΔMAC] mice. Additionally, CFA was found to upregulate the expression of AEG-1 and several PICs in the lumbar dorsal root ganglia of wild-type mice. However, in the absence of AEG-1, PIC expression mirrored vehicle controls. Lastly, AEG-1[ΔMAC] mice displayed a similar protective phenotype and PIC expression profile as AEG-1 KO mice. In summary, our results highlight for the first time the involvement of AEG-1 expression, particularly in myeloid cells, in the development of chronic inflammatory pain. Our results suggest the therapeutic potential of targeting AEG-1 for chronic inflammatory pain.

Inflammation has emerged as a compelling causal contributor to depression, serving both as a biological pathway underlying specific depressive symptoms (notably anhedonia, fatigue, and cognitive difficulties) and as a defining feature in a subtype of this disorder characterized by elevated levels of circulating cytokines. Understanding when and how immune dysfunction results in depression within clinical trials is needed to advance biomarker-guided clinical research and to accelerate novels treatments for those suffering from depression. In this context, gut microbes and intestinal epithelial barrier (IEB) integrity directly influence systemic cytokine levels and peripheral immune activation-these immune signals, in turn, modulate neural circuits involved in mood, reward, and stress reactivity through several pathways. Many of these signals converge on the blood-brain barrier (BBB), the permeability of which regulates the entry of peripheral cytokines and immune cells into the central nervous system and consequently shapes neuroinflammatory responses that contribute to depressive symptoms. In this narrative review, we contend that immune-gut-brain system is critical for understanding mechanisms and potential treatments for inflammatory depression. We synthesize evidence linking inflammation to IEB and BBB permeability, summarize barrier biomarkers relevant for depression, and highlight future directions of research that focus on fortifying dual barrier dysfunction as a novel intervention target for inflammatory depression. By considering the inflammatory mechanisms that shape IEB and BBB integrity, the field will be positioned to identify upstream drivers of these sources of inflammation, refine mechanistic models of transdiagnostic symptoms relevant to inflammation (anhedonia, fatigue, executive dysfunction), and develop more targeted or personalized intervention strategies for those suffering from these conditions.

Depression is a highly heterogeneous disorder involving diverse biological systems and pathogenic pathways. Clinical and prospective studies have revealed that a substantial proportion of patients present with elevated peripheral and central inflammatory cytokines, a phenotype strongly associated with poor response to standard antidepressants. The complement system has emerged as a pivotal upstream mediator that drives pathological neuroinflammation in depressive disorders. Overactivation of complement signaling drives glial activation, aberrant synaptic elimination, blood-brain barrier disruption, and neural circuit dysfunction. This process involves synergistic interactions between the C1q-C3-CR3 signaling axis and key regulatory proteins, including the high-mobility group box 1 protein, triggering receptor expressed on myeloid cells 2, Galectin-3, and neuronal pentraxin 2. Interventions targeting the complement system and its interacting proteins offer novel avenues for the treatment of inflammatory depression. The review systematically summarizes recent advances in the pathophysiological mechanisms of inflammatory depression and highlights the potential of complement-directed therapeutic strategies, aiming to provide actionable targets and fresh insights for drug development against this condition.

Cisplatin-induced neuropathic pain (CINP) is a frequent and debilitating adverse effect of chemotherapy that can persist long after treatment cessation and remains poorly controlled by current therapies. Identifying the mechanisms that drive CINP is therefore critical for developing effective interventions. Cisplatin has been reported to cause mitochondrial dysfunction and promote the release of mitochondrial DNA (mtDNA) into the cytosol, putatively through BCL2 associated X protein (BAX) pores, thereby activating stimulator of interferon genes (STING), a cytosolic double stranded DNA sensor. We have previously shown that activating STING signaling in nociceptors can induce pain. Here, we tested whether cisplatin engages STING signaling in nociceptors and promotes neuropathic pain. In a mouse model of CINP induced by repeated cisplatin administration (2 mg per kg per day, intraperitoneally, for three consecutive days), we observed increased BAX mRNA expression and cytosolic double stranded DNA in dorsal root ganglion (DRG) tissues containing nociceptors. Genetic ablation of STING signaling, either globally (Sting[gt/gt]) or selectively in nociceptors, significantly attenuated CINP. Mechanistically, STING activation in nociceptors promoted neuropathic pain through induction of interleukin-6 (IL-6), independently of type I interferon pathways. Pharmacological inhibition of STING reduced CINP development and IL-6 upregulation and prevented epidermal sensory fiber loss. Together, these findings identify a previously unrecognized pronociceptive role for STING signaling in nociceptors during CINP and support peripheral STING inhibition as a therapeutic strategy.

Biofluid proteins are promising transdiagnostic markers for delineating disease heterogeneity in psychosis. This study examined proteomic profiles in a transdiagnostic early psychosis sample to test the hypothesis that psychosis is associated with proteomic signatures of premature aging. We analyzed proteomic data from 85 individuals with early psychosis and 35 healthy controls from the Human Connectome Project for Early Psychosis (HCP-EP), using the Olink platform across four validated panels (Cardiometabolic, Inflammation, Cardiovascular II, and III). Our dual analytic strategy included: (1) calculating an index based on senescence-associated secretory phenotype (SASP) proteins to assess cellular aging, and (2) analyzing all 374 proteins using Gene Set Enrichment Analysis to identify whether predefined biological pathways are collectively enriched. We compared the SASP index and enriched pathways between groups and examined associations with sociodemographic, physical health, cognitive, psychological well-being, psychosocial functioning, symptom, and medication data. The SASP index was significantly elevated in the psychosis group. Pathway analyses revealed enrichment of two inflammation-related pathways in psychosis after multiple comparison correction: Cellular Response to Tumor Necrosis Factor and Monocyte Chemotaxis. The higher SASP index and the enriched inflammatory pathways were associated with increased body mass index (BMI) and reduced psychological well-being. Our findings are consistent with prior research linking psychosis to premature aging and an increased inflammation response. They also underscore the value of examining multiple biomarkers and biological pathways simultaneously and highlight the importance of conceptualizing psychosis as a whole-body condition. However, given the sample size, results should be considered preliminary. Larger, longitudinal studies are needed to track proteomic changes over time and assess the predictive value of these biomarkers for identifying vulnerable individuals and clinical outcomes.

Immune system activation contributes to the pathophysiology of multiple psychiatric disorders, including schizophrenia. A substantial subgroup of people with schizophrenia are characterised by increased central and peripheral cytokine levels, and a tendency towards more severe symptoms and dopamine-targeting antipsychotic treatment resistance. Previous studies have shown an association between inflammation and increased dopamine turnover as well as increased sensitivity to stimulants such as dextroamphetamine (DEX). However, thus far, no study has demonstrated that increased dopamine release is responsible for stimulant-induced psychosis-relevant behaviour during inflammatory states. This calls the role of dopamine in inflammatory schizophrenia into question. To test whether inflammation-exacerbated behavioural responses are driven by dopaminergic mechanisms, we used a multimodal approach in a mouse model combining intraperitoneally (i.p) administered DEX (0.5 mg kg[-1])-evoked open-field behaviour, in vivo dopamine monitoring, molecular and c-Fos profiling of dopamine-relevant brain regions using qPCR and immunostaining. We measured blood-brain barrier permeability and central DEX exposure in brain after DEX via fluorescein uptake and liquid chromatography-mass spectrometry. To induce inflammation, we administered two doses of lipopolysaccharide (LPS, 0.83 mg kg[-1]i.p.) or phosphate-buffered saline (PBS i.p.) to male C57BL/6J mice (n = 158) 24 h apart and measured neuro-behavioural outcomes from 72 to 74 h. Sickness responses, including body mass change, body condition, and inactivity, were assessed longitudinally to confirm resolution of LPS-induced sickness prior to DEX-evoked behavioural testing. In parallel, inflammatory and kynurenine pathway markers were measured in the ventral midbrain and striatum to determine whether persistent neuroinflammatory and metabolic alterations remained after sickness behaviours had subsided and could contribute to exaggerated psychosis-relevant behavioural responses. We found that LPS-treated mice exhibited significantly greater DEX-evoked locomotor activity than PBS-treated controls, despite no differences in whole-brain DEX concentrations. Neuronal activation, indexed by c-Fos[+] cell density, was significantly increased in both the dorsal and ventral striatum of LPS-treated mice. However, real-time ventral striatal dopamine dynamics assessed using fibre photometry, together with dopamine-related mRNA expression in the ventral midbrain and striatum, did not differ between treatment groups. In contrast, mRNA levels of inflammatory markers (IL-1β, TNF, NF-κB2) were upregulated. To explore alternative pathways through which behaviour may be affected, we measured mRNA levels of enzymes in the inflammation-induced kynurenine pathway. We found that dysregulation of mRNA levels of all three measured kynurenine pathway enzymes (TDO2, KAT II, KMO) was present in the LPS group following behavioural testing. Taken together, our findings suggest that while inflammation augments psychosis-relevant mouse behaviour, dopamine may not be the key driver.

In response to the Letter by Song and Luan, we clarify the route and rationale of interleukin-4 (IL-4) administration in our published study. Recombinant mouse IL-4 was administered intracerebroventricularly as a mechanistic intervention to engage central IL-4/STAT6 signaling, whereas the reference to systemic administration in Section 4.4 was intended to describe systemic CGRP receptor blockade. We further clarify the intracerebroventricular procedure, including guide cannula implantation, anesthesia, recovery, and subsequent IL-4 administration. We also acknowledge that the non-IL-4 groups did not undergo matched guide-cannula implantation or intracerebroventricular vehicle administration, which represents a limitation when interpreting the in vivo effects specifically associated with IL-4. These clarifications define the appropriate scope of interpretation of the in vivo IL-4 findings.