Background Studies indicate an association between pain perception and inflammatory response. However, the expression of inflammatory cytokines in the regulation of the interaction between pain and other coexisting symptoms related to pain, such as fatigue, remains largely unknown. Aim This study utilizes a comprehensive screening method for inflammatory biomarkers to objectively study their relation to fatigue and other patient reported outcomes, such as depression and sleep disturbances, in a cohort entailing patients with chronic pain and controls reporting no pain. Material and methods 36 patients with chronic pain and 36 healthy pain free controls were included. To investigate possible differences between patients and controls, the QUICKPLEX SQ 120 with a panel of 71 pro- and anti-inflammatory proteins was used. Patient reported data covering aspects of fatigue, fatigability, mood and sleep was also administered. Results No apparent difference in abundance of inflammatory substances was found between patients and controls. Likewise, no association was between levels of inflammatory biomarkers and performance on objectively measured cognitive fatigability. However, an explorative multivariate PCA analysis with immunological response as the determinant revealed five specific clusters, two clusters of controls and three patient clusters. One patient cluster had an overall lower concentration level of inflammatory substances compared to the other clusters. This cluster reported higher levels of general fatigue (trait fatigue) and state fatigue as well as higher proportions of pain localizations, perceived helplessness, insomnia, depressive symptoms, and anxiety. Conclusion This study underscores the complexity of pain perception and its interplay with inflammatory responses, as well as the individual experience of fatigue and other co-occurring symptoms. We argue that patients with chronic pain do not constitute a homogeneous group, and that simple patient–control comparisons may be insufficient to elucidate the underlying inflammatory processes involved. Our findings suggest that chronic pain patients who report higher levels of fatigue, sleep disturbances, and depressive symptoms might exhibit inflammatory response proteins associated with tissue-repair mechanisms. We speculate that this pattern could indicate a response driven more by central pain mechanisms.
Acute psychosocial stress triggers coordinated neuroendocrine and immune responses, yet the temporal coupling between cortisol release and leukocyte redistribution in humans remains understudied. In a sample of 302 participants (aged 18 to 59 years; 64 % female) drawn from the Swedish Twin Registry, we characterized trajectories of neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio (NLR) following the Trier Social Stress Test (TSST). Blood samples were collected at five timepoints (pre-stress, and at 5, 30, 60, and 90 min after stress), and plasma cortisol was measured at the first three timepoints. Linear mixed-effects models assessed the effects of time, cortisol response (area under the curve with respect to increase; AUCi), and covariates (sex, age, body mass index; BMI) on leukocyte dynamics. The TSST induced canonical biphasic leukocyte responses: lymphocytes peaked 5 min post-stress and declined below baseline during recovery, while neutrophils showed sustained late-phase elevations. Higher cortisol responses were associated with stronger late lymphocyte suppression and higher NLR at 30 to 90 min after stress, but largely unrelated to neutrophil trajectories. Male participants exhibited greater cortisol reactivity and higher late NLR, older age was associated with blunted cortisol and neutrophil recovery, and higher BMI with attenuated early lymphocyte responses. These findings delineate a plausible phase-specific endocrine-immune coupling in humans where cortisol is linked to variation in lymphocyte redistribution and NLR fluctuations following acute stress. The results suggest a mechanism by which heightened or recurrent HPA-axis activation could influence post-stress inflammatory tone, plausibly contributing to vulnerability for stress-related psychiatric disorders.
Background:Early detection of individuals at risk for clinical deterioration in first-episode psychosis (FEP) remains a vital challenge in psychiatric care. Emerging evidence indicates that immune dysregulation might play a crucial role in the pathophysiology and progression of psychotic disorders. This study examined associations between a plasma cytokine and chemokine panel and clinical stage transition in FEP patients. Methods:Using multiplex immunoassays, plasma samples from a small cohort of 35 FEP patients were screened for the quantification of 21 analytes. Participants were clinically assessed at baseline and follow-up and classified according to a validated staging model. Data were used to assess associations with clinical stability over a 12-month follow-up period. Results:IL-17A was increased in transitioning patients (uncorrected p = 0.045; adjusted p = 0.64 after correction for multiple comparisons). A logistic regression model combining IL-17A, IFN-γ and MIP-3α discriminated between groups with an AUC of 0.853 in this exploratory cohort. Conclusions:These findings highlight the potential relevance of neuroimmune mechanisms in the development of psychotic disorders and suggest that immunological markers may merit further consideration within staging-based models of care, pending external validation. Incorporating cytokine profiling into clinical practice may potentially inform personalized treatment strategies and lead to better long-term outcomes for individuals with FEP.
Background:Preclinical and postmortem human studies demonstrate significant opioid-related alterations in the neuroimmune system. However, studies investigating the neuroimmune system in living people with opioid use disorder (OUD) are lacking, thereby motivating this pilot study. Methods:Individuals with OUD (n = 6; DSM-5 criteria) were admitted inpatient and stabilized on an individualized buprenorphine dose for 5 to 10 days before a 120-min Positron Emission Tomography (PET) [11C]PBR28 scan. Using multilinear analysis-1 (MA-1; t* = 30), total volume of distribution (V T; 'TSPO availability') was estimated in 10 brain regions of interest (ROIs) incorporating the metabolite-corrected arterial input function. Demographically-matched non-OUD comparators (n = 18) underwent identical PET imaging procedures. Group differences in regional [11C]PBR28 V T were evaluated using linear mixed effects models. Partial correlations, controlling for rs6971 genotype, investigated relationships between regional [11C]PBR28 V T and subjective, behavioral, and biomarker data. Results:OUD participants exhibited higher brain TSPO availability by 20% across ROIs, on average (range: 12-22%) relative to non-OUD comparators (Group Effect; p = 0.036) whereas plasma cytokine/chemokine levels did not differ (ps > 0.05). Greater opioid craving correlated with higher TSPO availability in the parietal (r=0.82, p = 0.048) and prefrontal cortices (r=0.80, p = 0.059). Longer treatment duration correlated with lower TSPO availability in the prefrontal cortex (r = -0.93, p = 0.024). Conclusions:Results are the first exploratory evidence that living participants with OUD, stabilized on buprenorphine inpatient, exhibit elevated TSPO availability, an in vivo neuroimmune marker. TSPO availability was positively correlated with opioid craving and negatively correlated with treatment duration. While preliminary, our findings suggest that the neuroimmune system may be a therapeutic target in OUD.
Interleukin-33 (IL-33) is recognised both as an epithelial alarmin in type 2 barrier inflammation and as an astrocyte-, neuron-, and microglial-linked signal that licenses synapse and extracellular-matrix remodelling in the central nervous system (CNS). These two literatures have largely developed in parallel despite a shared logic: in both settings, a tissue-resident structural cell senses local stress, mobilises a nuclear alarmin, and instructs a resident ST2-responsive effector compartment to remodel the local niche. Here I propose a Reader–Alarmin–Effector framework for IL-33 biology at boundary tissues. Astrocytes and keratinocytes are not treated as equivalent cell types but as functionally convergent Readers: resident stress-integrating cells positioned to convert local disturbance into niche-level state change. Microglia in the CNS and a mast-cell-centred ST2-responsive effector field in skin provide parallel, but non-identical, Effector modules; recent evidence indicates that the CNS Reader–Effector relationship is reciprocal, with microglial ST2 signalling driving amphiregulin production that feeds back onto astrocytic EGFR (Wheeler et al., 2023).The framework may help explain why a similar IL-33-centred architecture is associated with divergent tissue outputs. In the CNS, the relative longevity of Reader and Effector cells may permit more cell-autonomous storage of inflammatory state and favour subtractive remodelling such as synaptic refinement, although reactive gliosis and matrix deposition also occur in pathological contexts. In skin, short-lived suprabasal keratinocytes may transfer inflammatory information to longer-lived carriers, including basal and bulge stem cells, Langerhans cells, tissue-resident memory T cells, mast cells, and sensory afferents; this handoff could favour additive remodelling such as hyperinnervation, cellular accumulation, and matrix deposition. This turnover asymmetry motivates a three-threshold working model of chronicity — effector activation, reader reprogramming, and structural persistence — that is presented as experimentally separable layers rather than an obligatory temporal sequence. The model generates testable predictions for single-cell and spatial profiling and links CNS synaptic set-points with chronic itch and sensory amplification within a shared brain–behavior–immunity framework.
