Inflammation Research Foundation

Chronic inflammatory and autoimmune conditions frequently manifest as multi-organ dysfunction without a single explanatory lens that integrates metabolic stress, innate immune activation, transcriptional control, and autonomic regulation. Here, we propose the Bio-Intelligence Circuit (BIC) as a hypothesis-generating systems framework connecting mitochondrial dysfunction, LPS–TLR4–NF-κB innate immune signaling, nuclear receptor dysregulation, and vagal reflex imbalance as interacting regulatory failure patterns that may sustain chronic inflammatory states. The central hypothesis is that loss of coordinated energetic, immune-sensing, and neuro-autonomic regulation sustains a self-reinforcing dysregulation loop that amplifies inflammatory signaling, impairs regulatory restraint, and limits recovery potential. Within this framework, we introduce Informational Bio-Recalibration (IBR) as a hypothesis-generating transition sequence in which improvement of mitochondrial bioenergetics and redox buffering, attenuation of excessive TLR4 signaling, restoration of nuclear receptor transcriptional coordination, and rebalancing of autonomic tone may together shift the system toward resolution-permissive physiology. This article does not report interventional outcomes; rather, it provides a structured conceptual model and testable predictions to guide future experimental validation across inflammatory and immune-mediated phenotypes.

Astrocytes are the main structural cells of the brain and spinal cord. Tessellating throughout the entire tissue, these highly arborized cells form intimate connections with each other and with essentially all other cell types in the CNS, including neurons, other glia such as microglia and oligodendrocyte-lineage cells, blood vessel cells, pial epithelium, and peripheral immune cells, when present. However, far more than inert cells gluing the CNS together, astrocytes are diverse and dynamic. Through their connections, they adapt and respond to local tissue cues, influencing CNS homeostasis and pathology. Yet, astrocyte biology is only superficially appreciated in clinical spheres. In this article, we briefly review some of the major facets of astrocyte biology as relevant to various neuroinflammatory diseases, including multiple sclerosis, myelin oligodendrocyte glycoprotein antibody–associated disorders, neuromyelitis optica spectrum disorders, anti–glial fibrillary acidic protein autoimmune encephalitis, and other neuroimmune conditions, highlighting their clinical and biological significance.

Major depressive disorder (MDD) is a multifaceted psychiatric illness with profound global consequences. To illuminate its molecular underpinnings, we employed a genome-driven integrative systems neuroimmunology approach to analyze transcriptomic profiles from 3114 individuals (1877 MDD patients and 1237 controls). This analysis uncovered coordinated neuroimmune transcriptomic shifts, marked by altered expression of genes involved in innate immune regulation, suppression of inflammatory responses, and pathways related to sensory perception, visual system development, and synaptic signaling. These alterations were consistently observed in both peripheral blood leukocytes (PBLs) and brain regions implicated in MDD. Among 31 genes jointly dysregulated in blood and brain, four stood out as robust predictors of MDD in PBLs: NEGR1, PPP6C, SORCS3, and PAX6. Of these, PAX6, a gene previously linked to MDD by GWAS, also exhibited differential expression in the amygdala and was functionally enriched in pathways governing immune modulation, vesicle trafficking, and neurodevelopmental processes, such as neuronal fate determination. In contrast, NEGR1, PPP6C, and SORCS3 showed no significant changes in brain expression, suggesting a predominantly peripheral role. Importantly, these transcriptomic insights were reinforced in a murine model of chronic stress, where immunophenotyping revealed elevated PAX6 expression in peripheral myeloid cells. Together, these findings reveal a shared neuroimmune signature across the brain and immune system in MDD, highlighting PAX6 as a promising mechanistic link and potential biomarker for this disorder.

<bold>Background:</bold> The relationship between FeNO levels and lung function over time is not well known. <bold>Aims and Objectives:</bold> To explore the relationship between patterns of FeNO over time and lung function trajectories. <bold>Methods:</bold> We used historical control-arm from 2 trials of uncontrolled asthma including 746 participants on stable medium to high dose ICS over 52 weeks in the TransCelerate database. Trajectories of change in FeNO were clustered using a machine learning Fuzzy algorithm. Lung function trajectories were defined as pre-bronchodilator FEV1 mixed effects slopes. The association between FeNO clusters and lung function slopes was assessed in a multiple linear regression model adjusting for relevant covariates. <bold>Results:</bold> Two distinct FeNO clusters were identified (Fig 1A), persistently stable (Cluster 1) and persistently declining FeNO over time (Cluster 2). Participants with persistently stable FeNO had a significantly lower rate of lung function improvement than those with persistently declining FeNO (Fig 1B, difference = 36.5 mL/year, p < 0.05). <bold>Conclusions:</bold> FeNO persistence patterns over time may predict lung function behavior in uncontrolled asthma. Persistent elevation in FeNO despite stable ICS use may indicate relative steroid resistance. Further studies are needed to evaluate if these patients would benefit from add-on therapy with Type 2 directed biologics. <fig><object-id>erj;66/suppl_69/PA1491/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>

Human airways contain specialized rare epithelial cells including CFTR-rich ionocytes that regulate airway surface physiology and chemosensory tuft cells that produce asthma-associated inflammatory mediators. Here, using a lung cell atlas of 311,748 single cell RNA-Seq profiles, we identify 687 ionocytes (0.45%). In contrast to prior reports claiming a lack of ionocytes in the small airways, we demonstrate that ionocytes are present in small and large airways in similar proportions. Surprisingly, we find only 3 mature tuft cells (0.002%), and demonstrate that previously annotated tuft-like cells are instead highly replicative progenitor cells. These tuft-ionocyte progenitor (TIP) cells produce ionocytes as a default lineage. However, Type 2 and Type 17 cytokines divert TIP cell lineage in vitro, resulting in the production of mature tuft cells at the expense of ionocyte differentiation. Our dataset thus provides an updated understanding of airway rare cell composition, and further suggests that clinically relevant cytokines may skew the composition of disease-relevant rare cells.

Traumatic brain injury (TBI) causes neuroinflammation and can generate long-term pathological consequences, including motor and visual impairments, cognitive deficits, and depression. In our previous study, we found that Fat1+-transgenic mice with higher endogenous n-3 polyunsaturated fatty acids (n-3 PUFA) were protected from post-TBI behavioral deficits and exhibited reduced levels of TBI-induced microglial activation, inflammatory factors, and sphingolipid ceramide, a lipid mediator of inflammation and cell death. This study’s objective was to evaluate if feeding n-3 PUFA (EPA and docosahexaenoic acid, DHA 2:1) could restrict the elevation of ceramide in brain tissue and prevent TBI-mediated sensory-motor and behavioral deficits. Wildtype C57/BL6 mice were gavage pre-fed with PUFA (EPA: DHA = 2:1) at 500 mg/kg body weight/week for 2 weeks before and 4 weeks after exposure to left side focal cranial air-blast (50 psi) TBI or sham-blast (0-psi). Saline-gavaged mice served as controls. Following blast injury, various motor, visual, and behavioral tests were conducted, and brain tissues were collected for histological and biochemical assays. Lipidomics analysis confirmed a significant elevation of EPA in the plasma and brain tissue of PUFA-fed mice. TBI-Blast brain tissues were found to have elevated ceramide levels in control mice but not in PUFA-fed mice. Moreover, PUFA-fed mice demonstrated protection against motor impairment, photoreceptor dysfunction, depression, oculomotor nerve degeneration, and microglia activation in the optic tract. Our results demonstrate that EPA-mediated suppression of ceramide biosynthesis and neuroinflammatory factors in PUFA-fed mice is associated with significant protection against the visual, motor, and emotional deficits caused by TBI.

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled disease-specific and common cell-cell communications involved in chemotaxis and extravasation to shed light on shared immune responses across tissues and diseases. Further, we performed experimental validation of two understudied cell-cell communications. Insights gleaned from this meta-analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.