Insulin resistance (IR) is a serious clinical syndrome that establishes the basis for illnesses like type 2 diabetes (T2D). In this study, the effectiveness of molsidomine (MOLS) which is a nitric oxide (NO) doner, on dexamethasone (DEXA)- induced IR in rats was examined. Male Wistar rats were managed with MOLS (5 and 10 mg/kg) orally once daily for 7 days before DEXA injection (1 mg/kg, intraperitoneally (i.p.)) and 7 days concurrent with DEXA injection. The findings showed that MOLS reduced low-density lipoprotein cholesterol (LDL-C), fasting serum glucose and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), alanine transaminase (ALT), aspartate transaminase (AST), oral glucose tolerance test (OGTT), and triglycerides (TGs). These findings revealed that MOLS was successful in reducing DEXA-induced IR. Moreover, MOLS was associated with a large increase in reduced glutathione (GSH) and superoxide dismutase (SOD) activity as well as a significant decrease in the levels of malondialdehyde (MDA) in hepatic and aortic tissues. When compared to rats treated with DEXA, MOLS significantly decreased the levels of pro-inflammatory cytokine interlukin-6 (IL-6), high mobility group box 1 (HMGB1), phosphorylated Janus kinase1/phosphorylated signal transducer and activator of transcription 3 (p-JAK1/p-STAT3), and nuclear factor kappa-B-p65 subunit (NF-κB-p65) in hepatic tissues. Additionally, MOLS reduced inflammation and necrosis and increased B cell/lymphoma 2 (BCL-2) and lowered caspase-3 levels and attenuated liver histopathological changes. Moreover, aortic expression levels of NF-κB-p65 and IL-6 were reduced upon MOLS treatment. All these findings show that MOLS protects rats from DEXA-induced IR by inhibiting HMGB1/JAK1/STAT3 signaling, regulating oxidative stress and inflammatory pathways, and having an antioxidant and anti-inflammatory effect.

Traumatic brain injury (TBI) triggers a complex neuroinflammatory cascade, with microglia serving as key regulators of both pathological damage and tissue structural restoration. Despite extensive research, the precise temporal evolution of microglial activation and its implications for long-term neurological outcomes remain incompletely understood. Here, we provide a comprehensive review of the molecular and cellular mechanisms underlying microglial responses in TBI, highlighting their role in neuroinflammation, neurogenesis, and tissue remodeling. We systematically compare clinical and preclinical TBI classifications, lesion patterns, and animal modeling strategies, evaluating their translational relevance. Furthermore, we explore the limitations of the conventional M1/M2 dichotomy and emphasize recent insights from single-cell transcriptomic analyses that reveal distinct microglial subpopulations across different injury phases. Finally, we discuss current therapeutic strategies targeting microglial modulation and propose future directions for neuroimmune interventions in TBI. By integrating findings from experimental and clinical studies, this review aims to bridge mechanistic insights with therapeutic advancements, paving the way for precision-targeted neuroimmune therapies.

Sinusoidal obstruction syndrome (SOS) is a fatal liver condition resulting from sinusoidal endothelial cell injury and hepatocyte death, following liver or hematopoietic stem cell transplantation as well as chemotherapy. We showed evidence of platelet displacement and aggregation within the space of Disse in SOS. However, the relationship between platelets and hepatocyte death remains unclear. Using a mouse SOS model by intraperitoneal monocrotaline (270 mg/kg; a pyrrolizidine alkaloide plant toxin) administration, we observed positive stains for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase-3, which are markers for apoptosis, in the liver by immunohistochemistry. At 48 h of the SOS liver, aggregated platelets and hepatocytes around zone 3 were found to express Fas ligand (FasL) and Fas, respectively. Human peripheral blood platelets, when aggregated, could induce expression of FASL on themselves and then lead to apoptosis in co-cultured HepG2 cells. Treatment of recombinant soluble thrombomodulin (rTM), an anticoagulant and vascular endothelium-protective drug, prevented the hepatocyte death in the SOS mice. These findings suggest that the prevention of platelet aggregation is a potential therapeutic intervention against hepatocyte death and severe liver damage in SOS.

Necroptosis is a novel mode of cell death that differs from traditional apoptosis, characterized by distinct molecular mechanisms and physiopathological features. Recent research has increasingly underscored the pivotal role of necroptosis in various neurological diseases, including stroke, Alzheimer's disease and multiple sclerosis. A defining hallmark of these conditions is neuroinflammation, a complex inflammatory response that critically influences neuronal survival. This review provides a comprehensive analysis of the mechanistic underpinnings of necroptosis and its intricate interplay with neuroinflammation, exploring the interrelationship between the two processes and their impact on neurological disorders. In addition, we discuss potential therapeutic strategies that target the intervention of necroptosis and neuroinflammation, offering novel avenues for intervention. By deepening our understanding of these interconnected processes, the development of more effective treatments approaches holds significant promise for improving patient outcomes in neurological disorders.

Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.

The Wobbler mouse is a genetic model of familial amyotrophic lateral sclerosis. Wobblers show spinal cord neurodegeneration associated with gliosis, neuroinflammation, and demyelination. Like human neurodegenerative diseases, Wobblers show high levels of corticosterone in the blood and the nervous system. The role of glucocorticoids in neuropathology is suggested by the observation that pathological signs attenuate with treatment with glucocorticoid receptor (GR) antagonists/modulators. In the present study, we demonstrated in 5-month-old clinically afflicted Wobbler mice that the selective GR modulator CORT125329 decreased motoneuron degeneration, astro- and microgliosis, and levels of pro-inflammatory factors (HMGB1, toll-like receptor 4, tumor necrosis factor α, and its receptor). In addition, CORT125329 increased the acetylcholine-producing enzyme choline acetyltransferase, the neurotrophin brain-derived neurotrophic factor, and their cellular colocalization. Furthermore, the increased oligodendrocyte number and a healthier myelin ultrastructure are consistent with the enhanced axonal myelination after CORT125329 treatment. Finally, the high expression of immunoreactive protein and mRNA levels of aquaporin4 in Wobblers was decreased by CORT125329 treatment, implying this water channel is a glucocorticoid target involved in neuropathology. The beneficial effects of CORT125329 correlated with enhanced motor behavioral performance and trophic changes of the forelimbs. In conclusion, our results support further preclinical and clinical studies on GR modulators in sporadic amyotrophic lateral sclerosis.

It is unclear whether high mobility group protein B1 (HMGB1) is associated with the malignant characterization of hand, foot, and mouth disease (HFMD), and whether it plays a key regulatory role in the process of enterovirus 71 (EV71)-induced brain damage. Firstly, we analyzed the correlation between clinical information and HMGB1 concentrations in patients with mild and severe HFMD. Immunofluorescence was used to determine the expression level of HMGB1 in astrocytes. The levels of cellular inflammatory factors (IL-1β, IL-4, IL-6, TNF-α and TGF-β1), chemokines (CCL2, CXCL10 and CXCL12) and adhesion factors (integrin β, P-gp, VCAM-1 and ICAM-1) were detected by ELISA kits. Western blot was used to measure the levels of blood-brain barrier (BBB) stability related factors (retinoic acid (RA), ANG1, ApoE and IGF-1) in astrocytes and BBB structure related proteins (occluding, claudin, PTCH-1 and ZO-1) in endothelial cells. Clinical studies found that the expression of HMGB1 was closely related to the HFMD severity. Knockdown of HMGB1 alleviated EV71-induced neuron damage and inhibited cellular inflammation and apoptosis. Importantly, silencing HMGB1 depressed excessive proliferation and the inflammation response of astrocytes caused by EV71 infection. Furthermore, knockdown of HMGB1 enhanced BBB stability by improving astrocyte adhesion and endothelial tight junctions. Mechanistically, HMGB1 regulated the stability of BBB by regulating sHh signaling and secretion in astrocytes. In conclusion, the level of HMGB1 is closely related to the clinical symptoms of patients with HFMD, and inhibiting the expression of HMGB1 promotes BBB stability by promoting sHh signaling in astrocytes.

Curcumin has strong anti-inflammatory properties and promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The aim of this study was to explore the role and potential molecular mechanism of curcumin in ameliorating osteogenic differentiation disorders caused by inflammation. We used LPS to induce an inflammatory response in hBMSCs. The expression of related mRNAs and proteins was detected by RT‒qPCR, Western blotting, immunofluorescence, and ELISA. The osteogenic differentiation of hBMSCs was detected by alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining. The results showed that after LPS treatment, the levels of the inflammatory cytokines TNF-α, IL-6 and IL-1β in hBMSCs increased, and the activity of ALP, the level of calcium salt deposition and the expression levels of the osteogenic proteins Runx2, COL1, OCN and OPN significantly decreased. The curcumin treatment alleviated this effect. These results indicated that curcumin improved the LPS-induced inflammation and osteogenic differentiation disorder in hBMSCs. Further studies revealed that the therapeutic effect of curcumin was caused by the inhibition of HMGB1 expression. From a mechanistic perspective, curcumin inhibits LPS-induced inflammation by inhibiting the expression of HMGB1, thereby inhibiting the NF-κB pathway and activating the NRF2 pathway, thereby improving the disordered osteogenic differentiation of hBMSCs. In conclusion, curcumin can reduce the LPS-induced inflammation of hBMSCs and ameliorate their osteogenic differentiation disorders.

We investigated the effect of single-nucleotide polymorphisms (SNPs) in the high mobility group box 1 (HMGB1) gene on morbidity and mortality after liver transplantation (LT). Among 120 LT recipients and their living donors, the genotypes of HMGB1, and the SNPs rs2249825, rs1045411, rs1412125, and rs1360485 were determined. There were no significant associations between these four SNPs and the incidence of rejection or mortality. However, the incidence of early allograft dysfunction (EAD) (n = 43), which presents as functional insufficiency within 1 week of LT, was significantly higher in recipients with the GC + CC allele of rs2249825 (n = 17/34) than in those with the GG allele (n = 26/86) (p = 0.044). Although the impact of donor HMGB1 SNPs on the incidence of EAD was not statistically significant, recipients with the GC + CC allele of rs2249825 who received liver grafts from donors with the same genotype had the highest incidence of EAD (p = 0.052). In contrast, the donor TC + CC allele of rs1412125 was an independent risk factor for the development of sepsis (n = 33) in LT recipient (OR = 3.05, 95 % CI = 1.18-7.87, p = 0.021). Thus, the SNPs of the HMGB1 gene in either recipients or donors were not associated with mortality but influenced the incidence of EAD and sepsis, likely being a predictive biomarker for the risk of serious complications after LT.

Niemann-Pick Disease (NPD) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by the deficiency of acid sphingomyelinase (ASMD), which is encoded by the Smpd1 gene. ASMD impacts multiple organ systems in the body, including the cardiovascular system. This study is the first to characterize cardiac pathological changes in ASMD mice under baseline conditions, offering novel insights into the cardiac implications of NPD. Using histological analysis, biochemical assays, and echocardiography, we assessed cardiac pathological changes and function in Smpd1-/- mice compared to Smpd1+/+ littermate controls. Immunofluorescence and biochemical assays demonstrated that ASMD induced lysosomal dysfunction, as evidenced by the accumulation of lysosomal-associated membrane proteins, lysosomal protease, and autophagosomes in pericytes and cardiomyocytes. This lysosomal dysfunction was accompanied by pericytes and cardiomyocytes inflammation, characterized by increased expression of caspase1 and inflammatory cytokines, and infiltration of inflammatory cells in the cardiac tissues of Smpd1-/- mice. In addition, histological analysis revealed increased lipid deposition and cardiac steatosis, along with pericyte-to-myofibroblast transition (PMT) and interstitial fibrosis in Smpd1-/- mice. Moreover, echocardiography further demonstrated that Smpd1-/- mice developed coronary microvascular dysfunction (CMD), as evidenced by decreased coronary blood flow velocity and increased coronary arteriolar wall thickness. Additionally, these mice exhibited significant impairments in systolic and diastolic cardiac function, as shown by a reduced ejection fraction and prolonged left ventricular relaxation time constant (Tau value). These findings suggest that ASMD induces profound pathological changes and vascular dysfunction in the myocardium, potentially driven by mechanisms involving lysosomal dysfunction as well as both pericytes and cardiac inflammation. KEY MESSAGES: Lysosomal dysfunction in ASMD leads to impaired autophagic flux in cardiac pericytes ASMD causes cardiac inflammation with leukocyte and M2 macrophage infiltration Lipid buildup in the pericytes, fibroblasts and myocardium lead to cardiac steatosis Enhanced cardiac fibrosis in ASMD links to pericyte-to-myofibroblast transition ASMD results in coronary microvascular and diastolic and systolic cardiac dysfunction.

Trophoblast cells undergo ferroptosis in pregnancy-related diseases. HMGB1 participates in pathological ferroptosis. However, whether lipopolysaccharide (LPS) -mediated HMGB1 expression induces the ferroptosis of trophoblast cells and further spontaneous abortion (SA) remains unknown.

HMGB1 and ACSL4 expression were measured in villous tissues from 20 women with SA and 20 women with elective abortion. Human HTR-8/SVneo cells were treated with LPS to establish an in vitro abortion model. The hallmarks of ferroptosis including MDA, GSH, Fe2+ and ROS were detected using indicated assay kits.

The levels of HMGB1 and ACSL4 in villous tissues from SA women were significantly higher than those in the normal control group. HMGB1 interacts with and stabilizes ACSL4 to promote the ferroptosis of trophoblast cells. Conversely, HMGB1 and/or ACSL4 inhibition attenuated LPS-induced trophoblast cells ferroptosis.

An HMGB1/ACSL4 axis is engaged in LPS-induced ferroptosis of trophoblast cells, and may be targeted to design treatments preventing SA.

Dorsal switch protein 1 (DSP1) of insects and high mobility group box 1 (HMGB1) protein of vertebrates are homologous. Both HMGB1 and DSP1 act as damage-associated molecular pattern (DAMP) molecules. Previous studies reported that DSP1 plays a DAMP role in mealworm, Tenebrio molitor, by activating immune genes like antimicrobial peptides (AMPs), phospholipase A2 (PLA2), phenoloxidase (PO) and regulating nodulation. However, RNAi of Tm-DSP1 suppresses these genes and their immune responses. While the immune role of DSP1 is established, its function in growth, development and survivability of T. molitor larvae is unknown. This study was designed to assess the role of DSP1 in the above-mentioned aspects. Tm-DSP1 gene was expressed in all the developmental stages and tissues of T. molitor larvae. The highest expression was observed in L6 larval stage and fat body tissue. Tm-DSP1 detection by western blotting supports its expression in T. molitor samples. Following bacterial challenge, DSP1 expression was upregulated in immune-related tissues, including hemocyte, fat body, and midgut. Detection of increased DSP1 in bacteria-challenged plasma ensures the release of DSP1 in plasma from the cell nucleus of immune-challenged larvae. Additionally, RNAi knockdown of Tm-DSP1 led to reduced larval growth (body length) and development (body weight) of T. molitor larvae resulting in increased mortality of the larvae. These findings suggest that DSP1 regulates the growth, development, and survival of T. molitor. However, whether DSP1 directly plays a role in these physiological processes or whether it interrupts any other genes to achieve these effects is still unknown. Further study is required to clarify this issue.

Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.

  We aimed to examine both the expression levels of high mobility group box 1 (HMGB1) and vascular cell adhesion molecule-1 (VCAM-1) proteins in the placentas of pregnant women with gestational diabetes mellitus (GDM) and control groups by immunohistochemical (IHC) method.

  An experimental case-control study was conducted, including 40 pregnant women complicated with GDM and 40 healthy pregnant women. Placental tissues obtained following cesarean delivery were subjected to routine tissue monitoring. The placental sections were stained with VCAM-1 and HMGB1 immunostains and subjected to IHC examination under a light microscope. H-score (HS) was used to evaluate the results of IHC staining by semi-quantitative analysis. Pathway analysis in Cytoscape software identified GDM-associated proteins within HMGB1 and VCAM-1 interaction networks, followed by GO analysis to explore associated biological processes.

  Placental HGMB1 expression was significantly increased in the GDM group compared to the control group (p<0.001). However, placental VCAM-1 expression was found to be statistically similar in GDM and control groups (p=0.584). The shared 19 proteins were identified between HMGB1 and GDM, and 13 between VCAM-1 and GDM, with notable GO biological process terms such as immune system activation for HMGB1 and interleukin-6 regulation for VCAM-1 associated with GDM.

  We consider that GDM-related inflammation and oxidative stress may contribute to tissue damage and inflammation by increasing placental HMGB1 expression. The blockade of HMGB1 and its receptors might represent a promising therapeutic approach to control inflammation in GDM. Understanding the distinct roles of HMGB1 and VCAM-1 may provide valuable insights for the development of targeted therapies aimed at mitigating the inflammatory processes associated with GDM and improving maternal and fetal outcomes.

Niemann-Pick Disease (NPD) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by the deficiency of acid sphingomyelinase (ASMD), which is encoded by the Smpd1 gene. ASMD impacts multiple organ systems in the body, including the cardiovascular system. This study is the first to characterize cardiac pathological changes in ASMD mice under baseline conditions, offering novel insights into the cardiac implications of NPD. Using histological analysis, biochemical assays, and echocardiography, we assessed cardiac pathological changes and function in Smpd1 -/- mice compared to Smpd1 +/+ littermate controls. Immunofluorescence and biochemical assays demonstrated that ASMD induced lysosomal dysfunction, as evidenced by the accumulation of lysosomal-associated membrane proteins, lysosomal protease, and autophagosomes in pericytes and cardiomyocytes. This lysosomal dysfunction was accompanied by pericytes and cardiomyocytes inflammation, characterized by increased expression of caspase1 and inflammatory cytokines, and infiltration of inflammatory cells in the cardiac tissues of Smpd1 -/- mice. In addition, histological analysis revealed increased lipid deposition and cardiac steatosis, along with pericyte-to-myofibroblast transition (PMT) and interstitial fibrosis in Smpd1 -/- mice. Moreover, echocardiography further demonstrated that Smpd1 -/- mice developed coronary microvascular dysfunction (CMD), as evidenced by decreased coronary blood flow velocity and increased coronary arteriolar wall thickness. Additionally, these mice exhibited significant impairments in systolic and diastolic cardiac function, as shown by a reduced ejection fraction and prolonged left ventricular relaxation time constant (Tau value). These findings suggest that ASMD induces profound pathological changes and vascular dysfunction in the myocardium, potentially driven by mechanisms involving lysosomal dysfunction as well as both pericytes and cardiac inflammation.

Background: Cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) are widely used. Previous methods to reduce inflammation have shown inconsistent results. We developed a cytokine adsorption column using polymethyl methacrylate (PMMA) and investigated its anti-inflammatory effects during ECMO. Materials and Methods: Male Sprague-Dawley rats were divided into three groups (seven rats in each group): SHAM, ECMO, and ECMO with PMMA (PMMA group). Experiments comprised 180 min of cannulation only in the SHAM group and 60 min of ECMO followed by 120 min of observation in the ECMO and PMMA groups. PMMA adsorption was conducted from 30 min after ECMO initiation to completion in the PMMA group. Blood parameters and cytokines were measured during experiments. Lung tissues were collected after the experiment for evaluation of tissue edema. Results: The PMMA group showed significantly lower levels of tumor necrosis factor alpha (TNF-α) and interleukin(IL)-6 compared to the ECMO group at 120 min after completing ECMO. However, there were no significant differences in IL-10 levels between the ECMO group and the PMMA group at the same time points. Lung edema incidence was significantly lower in the PMMA group. Conclusions: The PMMA column effectively suppressed systemic inflammatory reactions during ECMO.

Miserocchi, Giuseppe. Physiopathology of high-altitude pulmonary edema. High Alt Med Biol. 26:1-12, 2025.-The air-blood barrier is well designed to accomplish the matching of gas diffusion with blood flow. This function is achieved by maintaining its thickness at ∼0.5 µm, a feature implying to keep extravascular lung water to the minimum. Exposure to hypobaric hypoxia, especially when associated with exercise, is a condition potentially leading to the development of the so-called high-altitude pulmonary edema (HAPE). This article presents a view of the physiopathology of HAPE by merging available data in humans exposed to high altitude with data from animal experimental approaches. A model is also presented to characterize HAPE nonsusceptible versus susceptible individuals based on the efficiency of alveolar-capillary oxygen uptake and estimated morphology of the air-blood barrier.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, primarily driven by inflammatory processes within the disc, particularly involving the infiltration and activity of macrophages. High Mobility Group Box 1 (HMGB1) has been identified as a crucial mediator in this inflammatory cascade, yet its precise role in macrophage-induced disc degeneration remains unclear. In this study, we employed a combination of in vivo and in vitro models, including genetically engineered mice with macrophage-specific overexpression of HMGB1, a rat model of IVDD, and cultured macrophages and nucleus pulposus cells (NPCs), to elucidate the role of HMGB1 in IVDD. Our findings reveal that HMGB1 overexpression in macrophages significantly accelerates IVDD progression by enhancing NF-κB activation and upregulating MMP3 expression in NPCs. Furthermore, the administration of glycyrrhizin (GL), an HMGB1 inhibitor, effectively mitigated these effects, delaying IVDD progression. This study not only uncovers the critical mechanisms by which HMGB1 regulates the interactions between macrophages and NPCs in the inflammatory microenvironment but also provides a theoretical framework for targeting HMGB1 as a potential therapeutic strategy for IVDD. Thus, our findings suggest a promising novel approach for the treatment of this condition.

A significant portion of adolescents suffer from mental illnesses and persistent pain due to repeated stress. The components of the nervous system that link stress and pain in early life remain unclear. Prior studies in adult mice implicated the innate immune system, specifically Toll-like receptors (TLRs), as critical for inducing long-term anxiety and pain-like behaviors in social defeat stress (SDS) models. In this work, we investigated the pain and anxiety behavioral phenotypes of wild-type and TLR4-deficient juvenile mice subjected to repeated SDS and evaluated the engagement of TLR4 by measuring dimerization in the spinal cord, dorsal root ganglia, and prefrontal cortex. Male juvenile (4-week-old) mice (C57BL/6J or Tlr4-/-) underwent six social defeat sessions with adult aggressor (CD1) mice. In WT mice, SDS promotes chronic mechanical allodynia and thermal hyperalgesia assessed via von Frey testing and the Hargreaves test, respectively. In parallel, the stressed WT mice exhibited transient anxiety-like behavior and long-lasting locomotor activity reduction in the open-field test. Tlr4-/--stressed animals were resistant to the induction of pain-like behavior but had a remnant of anxious behavior, spending less time in the center of the arena. In WT SDS, there were concordant robust increases in TLR4 dimerization in dorsal root ganglia macrophages and spinal cord microglia, indicating TLR4 activation. These results suggest that the chronic pain phenotype and locomotor impairment induced by SDS in juvenile mice depends on TLR4 engagement evidenced by dimerization in immune cells of the dorsal root ganglia and spinal cord.

Infectious diseases caused by fungi, viruses, or bacteria can have a profound impact on human cognition. This can be due to either direct spread to the central nervous system (CNS) or indirect neuroinflammation. Ultimately causing neuronal damage and even neurodegeneration. Deteriorations in cognition, such as poor encoding and attention deficits, have been reported secondary to infectious diseases. Preclinical studies have identified the underlying mechanisms of these infection-related cognitive effects, such as through blood-brain barrier (BBB) disruption and M1 microglial polarization. These mechanisms are spearheaded by inflammatory markers that are released/initiated by the pathogens over the course of the infection. Among them, the high mobility group box 1 (HMGB1) protein is a common biomarker implicated across several infection-related cognitive deficits. Understanding these effects and mechanisms is crucial for the development of strategies to prevent and treat infection-related cognitive impairment. This review will thus consolidate and elucidate the current knowledge on the potential role of HMGB1 as a therapeutic target for infection-related cognitive impairments. This review will not only advance scientific understanding but also have significant clinical and public health implications, especially considering recent global health challenges. Based on the selected articles, extracellular HMGB1, as opposed to intracellular HMGB1, acts as damage-associated molecular patterns (DAMPs) or alarmins when released in the peripheries secondary to inflammasome activation. Due to their low molecular weight, they then enter the CNS through routes such as retrograde transport along the afferent nerves, or simple diffusion across the impaired BBB. This results in further disruption of the brain microenvironment due to the dysregulation of other regulatory pathways. The outcome is structural neuronal changes and cognitive impairment. Given its key role in neuroinflammation, HMGB1 holds promise as both a biomarker for diagnostic detection and a potential therapeutic target candidate for preventing infection-related cognitive impairment.

Pulmonary fibrosis, a chronic progressive lung disorder, can be the result of previous acute inflammation-associated lung injury and involves a wide variety of inflammatory cells, causing the deposition of extracellular matrix (ECM) components in the lungs. Such lung injury is often associated with excessive neutrophil function and the formation of DNA networks in the lungs, which are also some of the most important factors for fibrosis development. Acute lung injury with subsequent fibrosis was initiated in C57Bl/6 mice by a single intranasal (i.n.) administration of LPS. Starting from day 14, human recombinant DNase I in the form of Pulmozyme for topical administration was instilled i.n. twice a week at a dose of 50 U/mouse. Cell-free DNA (cfDNA), DNase activity, and cell content were analyzed in blood serum and bronchoalveolar lavage fluid (BALF). Inflammatory and fibrotic changes in lung tissue were evaluated by histological analysis. The gene expression profile in spleen-derived neutrophils was analyzed by RT-qPCR. We demonstrated that Pulmozyme significantly reduced connective tissue expansion in the lungs. However, despite the reliable antifibrotic effect, complete resolution of inflammation in the respiratory system of mice treated with Pulmozyme was not achieved, possibly due to enhanced granulocyte recruitment and changes in the nuclear/mitochondrial cfDNA balance in the BALF. Moreover, Pulmozyme introduction caused the enrichment of the spleen-derived neutrophil population by those with an unusual phenotype, combining pro-inflammatory and anti-inflammatory features, which can also maintain lung inflammation. Pulmozyme can be considered a promising drug for lung fibrosis management; however, the therapy may be accompanied by residual inflammation.

A growing body of evidence indicates that nonglycemic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors play an important role in the protective effects of these drugs in diabetes, chronic kidney disease, and heart failure. In recent years, the anti-inflammatory potential of SGLT2 inhibitors has been actively studied. This review summarizes results of clinical and experimental studies on the anti-inflammatory activity of SGLT2 inhibitors, with a special focus on their effects on macrophages, key drivers of metabolic inflammation. In patients with type 2 diabetes, therapy with SGLT2 inhibitors reduces levels of inflammatory mediators. In diabetic and non-diabetic animal models, SGLT2 inhibitors control low-grade inflammation by suppressing inflammatory activation of tissue macrophages, recruitment of monocytes from the bloodstream, and macrophage polarization towards the M1 phenotype. The molecular mechanisms of the effects of SGLT2 inhibitors on macrophages include an attenuation of inflammasome activity and inhibition of the TLR4/NF-κB pathway, as well as modulation of other signaling pathways (AMPK, PI3K/Akt, ERK 1/2-MAPK, and JAKs/STAT). The review discusses the state-of-the-art concepts and prospects of further investigations that are needed to obtain a deeper insight into the mechanisms underlying the effects of SGLT2 inhibitors on the molecular, cellular, and physiological levels.

Cell death can terminate in plasma membrane rupture to release potent pro-inflammatory intracellular contents thereby contributing to inflammatory diseases. Cell rupture is an active process, mediated by the membrane protein ninjurin-1 (NINJ1) in pyroptosis, post-apoptosis lysis, ferroptosis, and forms of necrosis. Once activated, NINJ1 clusters into large oligomers within the membrane to initiate cellular lysis. Recent preclinical studies have demonstrated that inhibiting NINJ1 is a new strategy for treating immune-mediated diseases. Indeed, both small molecule inhibitors and neutralizing antibodies can target NINJ1 clustering to preserve plasma membrane integrity and mitigate disease pathogenesis. In this Perspective, we provide a summary of the current state of knowledge and recent developments in targeting cellular integrity during cell death through NINJ1 inhibition to treat inflammatory disease, with a focus on liver injury. As these NINJ1-mediated cell death pathways are pivotal in maintaining health and contribute to disease pathogenesis when dysregulated, the studies discussed within have broad implications across the immunologic basis of molecular medicine.

Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.

Influenza, as well as other respiratory viruses, can trigger local and systemic inflammation resulting in an overall "cytokine storm" that produces serious outcomes such as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We hypothesized that gene therapy platforms could be useful in these cases if the production of an anti-inflammatory protein reflects the intensity and duration of the inflammatory condition. The recombinant protein would be produced and released only in the presence of the inciting stimulus, avoiding immunosuppression or other unwanted side effects that may occur when treating infectious diseases with anti-inflammatory drugs. To test this hypothesis, we developed AdV.C3-Tat/HIV-Box A, an inflammation-inducible cassette that remains innocuous in the absence of inflammation but releases HMGB1 Box A, an antagonist of high mobility group box 1 (HMGB1), in response to inflammatory stimuli such as lipopolysaccharide (LPS) or influenza virus infection. We report here that this novel inflammation-inducible HMGB1 Box A construct in a non-replicative adenovirus (AdV) vector mitigates lung and systemic inflammation therapeutically in response to influenza infection. We anticipate that this strategy will apply to the treatment of multiple diseases in which HMGB1-mediated signaling is a central driver of inflammation.IMPORTANCEMany inflammatory diseases are mediated by the action of a host-derived protein, HMGB1, on Toll-like receptor 4 (TLR4) to elicit an inflammatory response. We have engineered a non-replicative AdV vector that produces HMGB1 Box A, an antagonist of HMGB1-induced inflammation, under the control of an endogenous complement component C3 (C3) promoter sequence, that is inducible by LPS and influenza in vitro and ex vivo in macrophages (Mϕ) and protects mice and cotton rats therapeutically against infection with mouse-adapted and human non-adapted influenza strains, respectively, in vivo. We anticipate that this novel strategy will apply to the treatment of multiple infectious and non-infectious diseases in which HMGB1-mediated TLR4 signaling is a central driver of inflammation.

This study aimed to investigate the diagnostic potential of serum high-mobility group box 1 (HMGB1) in neonatal encephalopathy (NE).

A retrospective study was conducted, analyzing 216 neonates diagnosed with NE. The neonates were divided into two groups based on their outcomes at 28 days. Serum HMGB1 levels were compared between the two groups. ROC analysis was used to determine the predictive value of HMGB1.

At 28 days, 174 infants had a good prognosis, while 42 had a poor prognosis. Infants with a poor prognosis had higher serum HMGB1 concentrations within 24 h of birth. Multifactorial analysis revealed that extremely preterm birth, extremely low birth weight, an Apgar score of 0-3 at 5 min, premature rupture of membranes by the mother, moderate to severe NE, and serum HMGB1 > 6.14 ng/mL are independent risk factors for poor prognosis. HMGB1 has predictive value for short-term prognosis with an area under the curve of 0.79. Elevated HMGB1 levels in the acute phase of NE are associated with poor short-term neonatal outcomes. The decrease in HMGB1 concentrations over time correlates with a good prognosis; whereas an increase suggests a poor prognosis.

Early measurement of serum HMGB1 could aid in the prognostic assessment of neonates with NE.

Although serum HMGB1 has emerged as a potential predictor of neonatal outcomes in neonatal encephalopathy, the relationship of HMGB1 levels to neonatal encephalopathy severity remains unclear. The current results demonstrate that infants with a poor prognosis had higher serum HMGB1 concentrations within 24 h of birth. Importantly, elevated serum HMGB1 levels in the acute phase of neonatal encephalopathy are associated with poor short-term neonatal outcomes. Our findings reveal the clinical values of HMGB1 in the prediction of neonatal outcomes in NE patients.

Rheumatoid arthritis (RA) is a chronic inflammatory disease where pain, driven by both inflammatory and non-inflammatory processes, is a major concern for patients. This pain can persist even after joint inflammation subsides. High mobility group box-1 (HMGB1) is a non-histone-DNA binding protein located in the nucleus that plays a key role in processes such as DNA transcription, recombination, and replication. HMGB1 can be released into the extracellular space through both passive and active mechanisms. Extracellular HMGB1 contributes to synovial inflammation, bone degradation, and the production of cytokines in RA by binding to toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE). It also forms complexes with molecules like lipopolysaccharide (LPS) and IL-1β, amplifying inflammatory responses. Due to its central role in these processes, HMGB1 is considered a promising therapeutic target in RA. It also acts as a nociceptive molecule in mediating pain in diseases such as diabetes and bone cancer. In this review, we explore how HMGB1 contributes to chronic pain in RA, supported by both in vitro and in vivo models. We begin by providing an overview of the mechanisms of pain in RA, the structure of HMGB1, its release mechanisms, and the therapeutic potential of targeting HMGB1 in RA. Following this, we highlight its role in peripheral and central pain sensitization through direct activation of the TLR4/MAPK/NF-κB pathway, as well as indirectly through downstream mediators, underscoring its potential as a target for managing RA pain.

Inflammation, driven by various stimuli such as pathogens, cellular damage, or vascular injury, plays a central role in numerous acute and chronic conditions. Current treatments are being re-evaluated, prompting interest in naturally occurring compounds like kaempferol, a flavonoid prevalent in fruits and vegetables, for their anti-inflammatory properties. This study explores the therapeutic potential of kaempferol, focusing on its ability to modulate pro-inflammatory cytokines and its broader effects on inflammatory signaling pathways. Comprehensive reviews of in vitro and in vivo studies were conducted to elucidate the mechanisms underlying its anti-inflammatory and antioxidant actions. Kaempferol effectively inhibits the production of key inflammatory mediators, including cytokines and enzymes such as COX-2 and iNOS, while also targeting oxidative stress pathways like Nrf2 activation. The compound demonstrated protective effects in various inflammatory conditions, including sepsis, neurodegenerative disorders, cardiovascular diseases, and autoimmune conditions, by modulating pathways such as NF-κB, MAPK, and STAT. Despite its promise, kaempferol's clinical application faces challenges related to its bioavailability and stability, underscoring the need for advanced formulation strategies. These findings position kaempferol as a promising candidate for anti-inflammatory therapy, with the potential to improve patient outcomes across a wide range of inflammatory diseases. Further clinical studies are required to validate its efficacy, optimize dosage, and address pharmacokinetic limitations.

Currently, the treatment of septic myopathy presents significant challenges with implications for increased mortality rates and prolonged hospitalizations. Effective therapeutic strategies for septic myopathy remain elusive, highlighting an urgent need for novel therapeutic approaches. High-mobility group box 1 (HMGB1) is a conserved nonhistone nuclear protein that is released passively from deceased cells or actively secreted by activated immune cells, influencing both infectious and noninfectious inflammatory responses. Studies have indicated that HMGB1 likely plays a pivotal role in the pathogenesis of septic myopathy by crucial pathways associated with muscle atrophy and contributing to muscle regeneration under certain conditions. This review aims to summarize the possible mechanisms of HMGB1 in muscle atrophy and its potential in muscle regeneration, providing a theoretical basis for HMGB1 treatment of septic myopathy. Research shows that the dual role of HMGB1 is related to its specific forms, which are influenced to varying degrees by environmental factors. HMGB1 is a key participant in septic muscle atrophy, whereas HMGB1 shows therapeutic potential in muscle regeneration. One key mechanism by which HMGB1 contributes to septic muscle atrophy is through the exacerbation of inflammation. HMGB1 can amplify the inflammatory response by promoting the release of pro-inflammatory cytokines, which further damages muscle tissue. HMGB1 is also involved in promoting cell death in sepsis, which contributes to muscle degradation. Another important mechanism is the regulation of protein degradation systems. HMGB1 can activate the ubiquitin-proteasome system and autophagy-lysosome pathway, both of which are crucial for the breakdown of muscle proteins during atrophy. Conversely, targeting HMGB1 has shown the potential to ameliorate muscle atrophy in various diseases. For instance, HMGB1 has been shown to promote muscle vascular regeneration, modify stem cell status and enhance stem cell migration and differentiation, all of which are beneficial for muscle repair and recovery. Pharmacological inhibition of HMGB1 has been explored, with several drugs demonstrating efficacy in reducing inflammation and muscle degradation in sepsis models. These findings suggest that HMGB1 inhibition could be a viable therapeutic approach for septic myopathy. However, the function of promoting muscle regeneration in septic myopathy needs further research. HMGB1 emerges as a promising therapeutic target for the treatment of muscle atrophy in sepsis. This review focuses on identifying the correlation between HMGB1 and septic myopathy, analysing the possible role of HMGB1 in disease development and examining the feasibility of HMGB1 as a therapeutic target.

Myocardial ischemia, resulting from coronary artery blockage, precipitates cardiac arrhythmias, myocardial structural changes, and heart failure. The pathophysiology of MI is mainly based on inflammation and cell death, which are essential in aggravating myocardial ischemia and reperfusion injury. Emerging research highlights the functionality of high mobility group box-1, a non-histone nucleoprotein functioning as a chromosomal stabilizer and inflammatory mediator. HMGB1's release into the extracellular compartment during ischemia acts as damage-associated molecular pattern, triggering immune reaction by pattern recognition receptors and exacerbating tissue inflammation. Its involvement in signaling pathways like PI3K/Akt, TLR4/NF-κB, and RAGE/HMGB1 underscores its significance in promoting angiogenesis, apoptosis, and reducing inflammation, which is crucial for MI treatment strategies. This review highlights the complex function of HMGB1 in the pathogenesis of myocardial infarction by summarizing novel findings on the protein in ischemic situations. Understanding the mechanisms underlying HMGB1 could widen the way to specific treatments that minimize the severity of MI and enhance patient outcomes.

Mitochondria are important organelles for cell metabolism and tissue survival. Their cell-to-cell transfer is important for the fate of recipient cells. Recently, bone marrow mesenchymal stem cells (BM-MSCs) have been reported to provide mitochondria to cancer cells and rescue mitochondrial dysfunction in cancer cells. However, the details of the mechanism have not yet been fully elucidated. In this study, we investigated the humoral factors inducing mitochondrial transfer (MT) and the mechanisms. BM-MSCs produced MT in colorectal cancer (CRC) cells damaged by 5-fluorouracil (5-FU), but were suppressed by the anti-high mobility group box-1 (HMGB1) antibody. BM-MSCs treated with oxidized HMGB1 had increased expression of MT-associated genes, whereas reduced HMGB1 did not. Inhibition of nuclear factor-κB, a downstream factor of HMGB1 signaling, significantly decreased MT-associated gene expression. CRC cells showed increased stemness and decreased 5-FU sensitivity in correlation with MT levels. In a mouse subcutaneous tumor model of CRC, 5-FU sensitivity decreased and stemness increased by the MT from host mouse BM-MSCs. These results suggest that oxidized HMGB1 induces MTs from MSCs to CRC cells and promotes cancer cell stemness. Targeting of oxidized HMGB1 may attenuate stemness of CRCs.

Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2). IAV-induced ICD cells enhance biomass-derived carbon (BMDCs) migration, antigen uptake, cross-presentation, and maturation in vitro. Furthermore, immunization with IAV-induced ICD cells effectively suppressed tumor growth in melanoma-bearing mice. The isolated cell membrane inherited the immunological characteristics from the ICD cells and elicited robust antitumor immune responses through decorating PLGA NPs loading with a tumor-specific helper T-cell peptide and supplemented with ATP in a hydrogel system. This study indicated a promising strategy for developing cell-based and personalized tumor vaccines through fully taking advantage of the immune stimulation mechanisms of ICD occurrence in tumor cells, IAV modification, and nanoscale delivery.

Bacterial meningitis (BM) is a life-threatening central nervous system infection with potential for severe neurological sequelae. High mobility group box 1 (HMGB1) is known as a late inflammatory mediator associated with lethal pathology. This study aims to investigate the serial cerebrospinal fluid (CSF) concentrations of HMGB1 in children with BM and its relationship to neurological prognosis.

This retrospective cohort study included children with BM, aseptic meningitis (AM), and controls. CSF samples were collected serially from patients with BM and once from those with AM and controls. HMGB1 and interleukin-6 (IL-6) concentrations were measured using ELISA and bead-based multiplex assays, respectively. Statistical analyses included Mann-Whitney U tests, Kruskal-Wallis tests, and three-way ANOVA to evaluate differences among groups and over time.

HMGB1 levels in the CSF of children with BM were significantly higher than in those with AM and controls (p < 0.001). Inflammatory cytokine IL-6 levels decreased after treatment; however, HMGB1 levels remained elevated in half of the BM patients. Notably, a patient with neurological sequelae exhibited a delayed elevation of HMGB1 until the latest time points. Three-way ANOVA revealed significant differences in the time course of IL-6 and HMGB1 among individuals (p = 0.018).

Elevated CSF HMGB1 levels persist in some children with BM even after treatment, particularly in those with poor neurological outcomes. These findings suggest that delayed elevation of HMGB1 may contribute to severe inflammation and poor prognosis in BM. Further research into HMGB1 as a potential therapeutic target in BM is warranted.

The Receptor for Advanced Glycation End Products (RAGE), part of the immunoglobulin superfamily, plays a significant role in various essential functions under both normal and pathological conditions, especially in the progression of Alzheimer's disease (AD). RAGE engages with several damage-associated molecular patterns (DAMPs), including advanced glycation end products (AGEs), beta-amyloid peptide (Aβ), high mobility group box 1 (HMGB1), and S100 calcium-binding proteins. This interaction impairs the brain's ability to clear Aβ, resulting in increased Aβ accumulation, neuronal injury, and mitochondrial dysfunction. This further promotes inflammatory responses and oxidative stress, ultimately leading to a range of age-related diseases. Given RAGE's significant role in AD, inhibitors that target RAGE and its ligands hold promise as new strategies for treating AD, offering new possibilities for alleviating and treating this serious neurodegenerative disease. This article reviews the various pathogenic mechanisms of AD and summarizes the literature on the interaction between RAGE and its ligands in various AD-related pathological processes, with a particular focus on the evidence and mechanisms by which RAGE interactions with AGEs, HMGB1, Aβ, and S100 proteins induce cognitive impairment in AD. Furthermore, the article discusses the principles of action of RAGE inhibitors and inhibitors targeting RAGE-ligand interactions, along with relevant clinical trials.

Previous studies have found that matrine (MAT) effectively treated Ulcerative Colitis (UC). The purpose of this study is to explore its mechanism based on the HMGB1/NLRP3/Caspase-1 signaling pathway.

MAT was administered intragastrically to DSS-induced UC mice for 14 days. The Disease Activity Index (DAI) and histological staining were measured to detect histopathological changes in colon. The levels of IL-1β, IL-6, and TNF-α in serum were measured by ELISA. The protein and mRNA expression of HMGB1/NLRP3/Caspase-1 in the colon were detected by immunohistochemistry, western Blotting or qRT-PCR.

MAT improved the histological pathological changes of UC mice, as assessed by DAI, colonic length, and colonic mucosal injury. MAT also reduced colonic inflammatory damage by reducing the serum IL-1β, IL-6, and TNF-α content and decreasing the expression of HMGB1, NLRP3, Caspase-1, and IL-1β and proteins and mRNA in the colon.

MAT could significantly alleviate DSS-induced UC symptoms by reducing the expressions of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, the mechanism of which is related to the inhibition of HMGB1/NLRP3/Caspase-1 signaling pathway.

In inflammatory bowel diseases (IBD), the most promising therapies targeting cytokines or immune cell trafficking demonstrate around 40% efficacy. As IBD is a multifactorial inflammation of the intestinal tract, a single-target approach is unlikely to solve this problem, necessitating an alternative strategy that addresses its variability. One approach often overlooked by the pharmaceutically driven therapeutic options is to address the impact of environmental factors. This is somewhat surprising considering that IBD is increasingly viewed as a condition heavily influenced by such factors, including diet, stress, and environmental pollution-often referred to as the "Western lifestyle". In IBD, intestinal responses result from a complex interplay among the genetic background of the patient, molecules, cells, and the local inflammatory microenvironment where danger- and microbe-associated molecular patterns (D/MAMPs) provide an adjuvant-rich environment. Through activating DAMP receptors, this array of pro-inflammatory factors can stimulate, for example, the NLRP3 inflammasome-a major amplifier of the inflammatory response in IBD, and various immune cells via non-specific bystander activation of myeloid cells (e.g., macrophages) and lymphocytes (e.g., tissue-resident memory T cells). Current single-target biological treatment approaches can dampen the immune response, but without reducing exposure to environmental factors of IBD, e.g., by changing diet (reducing ultra-processed foods), the adjuvant-rich landscape is never resolved and continues to drive intestinal mucosal dysregulation. Thus, such treatment approaches are not enough to put out the inflammatory fire. The resultant smoldering, low-grade inflammation diminishes physiological resilience of the intestinal (micro)environment, perpetuating the state of chronic disease. Therefore, our hypothesis posits that successful interventions for IBD must address the complexity of the disease by simultaneously targeting all modifiable aspects: innate immunity cytokines and microbiota, adaptive immunity cells and cytokines, and factors that relate to the (micro)environment. Thus the disease can be comprehensively treated across the nano-, meso-, and microscales, rather than with a focus on single targets. A broader perspective on IBD treatment that also includes options to adapt the DAMPing (micro)environment is warranted.