Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 μM in the serum of exposed individuals and at an average of 0.15 μM in the unexposed. DBT has been detected in human blood at levels up to 0.3 μM. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin-1 beta (IL-1β) and IL-6 are pro-inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL-1β and IL-6 by immune cells in a MAP kinase (MAPK) dependent process. Toll-like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP-induced production of IL-1β and IL-6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT-induced IL-6 production depends on TLR1/2, whereas IL-1β production does not. Blocking the TLR-linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL-1β and IL-6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro-inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.

COVID-19 mRNA vaccines have demonstrated 95 % efficacy in the general population. However, their immunogenicity in adolescents with Type 1 Diabetes (T1D), who exhibit weaken immune responses, remains insufficiently explored.

Longitudinal analysis of innate immune responses following PRR-agonists and BNT162b2 vaccine stimulations, along with S-specific antibody responses, memory T cell recall responses, and RNA-sequencing were assessed in eight T1D adolescents and 16 healthy controls at six different timepoints.

After BNT162b2 vaccination, T1D adolescents produced SARS-CoV-2-specific binding and neutralizing antibodies (Nabs) comparable to healthy controls. Lower pre-vaccination blood HbA1c level correlated with higher antibody responses among T1D adolescents. However, they exhibited impaired TLR9-induced B cells and the first vaccine-induced monocyte activation. These differences were supported by transcriptomic analysis, which revealed the impairment in innate immune-related signatures both before and after vaccination. One year post-second vaccination, T1D adolescents demonstrated compromised cross-protection of T cell against BA.1 compared to healthy controls, which correlated with impaired innate immune responses identified in this study.

This study reveals that while T1D adolescents vaccinated with the BNT162b2 vaccine develop robust S-specific antibodies, their cross-protective T cell responses are suboptimal.

Hepatic hemangiomas are typically asymptomatic benign liver tumors. This report describes a case of a large hepatic hemangioma with internal bleeding and necrosis, presenting as fever of unknown origin, which was successfully treated with surgical resection. A woman in her 40s presented with persistent fever and fatigue. Imaging revealed a 13 cm mass in the posterior sector of the right hepatic lobe, with areas of high attenuation suggestive of internal bleeding. Laboratory tests revealed elevated levels of C-reactive protein, interleukin-6, and complement components (C3, C4, and CH50), along with an increased erythrocyte sedimentation rate. Symptomatic treatment with antipyretic medications failed to resolve the fever; therefore, hepatic resection was performed for diagnostic and therapeutic purposes. Post-operative recovery was uneventful, and the fever resolved completely. Pathological examination revealed cavernous hemangioma with well-defined necrotic areas. Post-operative blood tests showed normalization of the preoperatively elevated prognostic markers. Bleeding and necrosis associated with a large hemangioma appear to trigger the release of damage-associated molecular patterns, stimulating interleukin 6 production, promoting prostaglandin E2 synthesis, and ultimately leading to fever. Hepatic resection is an effective treatment for large hemangiomas in patients presenting with fever.

The systemic immune inflammation (SII) index provides a comprehensive assessment of inflammatory and immune status in patients with different diseases. However, it remains unclear whether the SII can be considered a valuable prognostic risk factor of all-cause mortality for postmenopausal women.

We analyzed data from 1882 postmenopausal women enrolled in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. The Systemic Immune-Inflammation Index (SII) was calculated using peripheral blood cell counts and categorized into quartiles. Multivariable Cox proportional hazards models and restricted cubic spline analyses were employed to assess the association between SII and mortality outcomes.

Over a median follow-up period of 8 years, 13.5% individuals died, with 4% deaths attributed to CVD. Patients with extremely high SII levels experienced significantly higher all-cause and CVD mortality. Compared to the low SII group (Q1), the hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality risk were 0.96 (0.87, 1.07), 0.97 (0.88, 1.08), and 1.28 (1.16, 1.41) for Q2, Q3, and Q4, respectively. Similarly, the HR (95% CI) for CVD mortality in Q2, Q3, and Q4 were 1.02 (0.83, 1.24), 1.11 (0.92, 1.34), and 1.32 (1.10, 1.58), respectively. Including SII in addition to traditional risk factors resulted in a slight enhancement in mortality prediction capability.

Among postmenopausal women, extremely high SII levels were identified as an independent risk factor for all-cause and CVD mortality.

Chronic inflammation plays a central role in the pathogenesis of lung diseases including asthma, long COVID, chronic obstructive pulmonary disease (COPD), and lung cancer. Lipopolysaccharide (LPS) is a potent inflammatory agent produced by Gram-negative bacteria and also found in cigarette smoke. Our earlier study revealed that the intranasal exposure of A/J mice to LPS for 7 days altered gene expression levels in alveolar Type II epithelial cells (AECIIs), which serve as precursors to lung adenocarcinoma and are also preferentially targeted by SARS-CoV-2. In the present work, we employed a comprehensive multi-omics approach to characterize changes in DNA methylation/hydroxymethylation, gene expression, and global protein abundances in the AECIIs of A/J mice following the sub-chronic exposure to LPS and after a 4-week recovery period. Exposure to LPS led to hypermethylation at regulatory elements within the genome such as enhancer regions and expression changes in genes known to play a role in lung cancer tumorigenesis. Changes in protein abundance were consistent with an inflammatory phenotype and also included tumor suppressor proteins. Integration of the multi-omics data resulted in a model where LPS-driven inflammation in AECIIs triggers epigenetic changes that, along with genetic mutations, may contribute to lung cancer development.

Background/Objectives: Clinical experience indicates that the determination of interleukin 6 (IL-6) in human blood can vary depending on time span between sample collection and centrifugation. Here, we evaluated confounding effects in various blood specimens. Methods: The blood of healthy individuals and critically ill patients was collected in EDTA-, heparin-, and serum collection tubes. Tubes were facultatively incubated (20 °C, 24-48 h) before centrifugation, and IL-6 was measured in the supernatant. Results: The preincubation of the blood collection tubes increased the IL-6 values in heparin plasma (in 17/20 samples up to 50-fold) and serum (in 17/20 samples up to 12-fold). These changes were relevant since the normal values were thereby lifted above the upper confidence limit in 12/20 heparin plasma samples and 4/20 serum samples. These IL-6 increases were probably due to in vitro synthesis as opposed to the release of preformed IL-6 from blood cells because subjecting uncentrifuged collection tubes to mechanical cell lyses had negligible effects on IL-6, while incubation with microbial stimulators dramatically increased these values. In the case of EDTA blood, collection tube preincubation induced IL-6 decreases in 17/20 samples from healthy individuals and 20/23 samples from critically ill patients. Conclusions: IL-6 determination in heparin plasma and serum is compromised by delayed centrifugation. This effect is relevant for normal values. It increased the number of false high results by >50%. The delayed centrifugation of EDTA blood decreased the IL-6 values, which caused a single false-negative result in 1/43 healthy and critically ill people. The false-negative rate is possibly higher in EDTA blood from non-critically ill out-patients, exhibiting moderately increased IL-6 levels.

It is largely unknown whether the specific developmental stage at which childhood trauma occurs is related to inflammatory dysregulation in adulthood. We aimed to explore if trauma exposure at distinct developmental stages in childhood is differentially associated with the novel marker of chronic inflammation - soluble urokinase plasminogen activator receptor (suPAR), as well as with C-Reactive Protein (CRP) and Interleukin-6 (IL-6) levels in early adulthood.

Participants were drawn from the Avon Longitudinal Study of Parents and Children (n = 3272). The trauma variables represent any trauma exposure within early (0-4.9 years), middle (5-10.9 years), or late (11-17 years) childhood, and were derived from the responses to 121 questions collected via standardised questionnaires regarding traumatic experiences including physical abuse, sexual abuse, emotional abuse, emotional neglect, domestic violence, and bullying. Plasma suPAR, CRP and IL-6 samples were collected at age 24. Linear regression models assessed the relationship between trauma exposure at different developmental stages and the inflammatory markers, adjusting for sex, socio-economic status (SES) and child ethnicity. Latent profile analysis (LPA) identified age 24 inflammatory profiles and multinomial logistic regressions identified associations between childhood trauma and these latent groups.

After adjustment for confounders, late childhood trauma was significantly associated with age 24 suPAR (β = 0.06, 95 % CI [.03, 0.1], p = 0.001), CRP (β = 0.09, 95 % CI [.01, 0.17], p = 0.04) and IL-6 (β = 0.1, 95 % CI [.02, 0.19], p = 0.02). The relationship between late trauma and suPAR survived additional adjustment for prior trauma (β = 0.06, 95 % CI [.01, 0.11], p = 0.03). Middle childhood trauma was significantly associated with IL-6 (β = 0.1, 95 % CI [.02, 0.18], p = 0.02). This attenuated after additionally adjusting for prior trauma (β = 0.11, 95 % CI [-0.09, 0.3], p = 0.29). There was little evidence of an association between early trauma and any inflammatory marker. Exposure to any trauma from 0-17 years was associated with elevated suPAR (β = 0.04, 95 % CI [.005, 0.07], p = 0.025) and IL-6 (β = 0.1, 95 % CI [.02, 0.18], p = 0.02) after adjustment for confounders. Additionally, LPA identified three distinct inflammatory profiles: 1. no inflammatory dysregulation; 2. elevated CRP and IL-6 levels; and 3. a high inflammatory group characterised by elevated levels of suPAR, CRP and IL-6. After adjustment for confounders, individuals with trauma either in early (RR = 2.31, 95 % CI [1.16, 4.6], p = 0.017), middle (RR = 2.72, 95 % CI [1.4, 5.29], p = 0.003) or late (RR = 3.37, 95 % CI [1.7, 6.64], p < 0.001) childhood had an increased risk of being in the high inflammatory group. The association between late childhood trauma and this high inflammatory group survived adjustment for prior trauma (RR = 3.69, 95 % CI [1.44, 9.47], p = 0.007).

When the inflammatory markers were analysed independently, late childhood trauma showed a strong association with age 24 suPAR levels after adjusting for confounders and prior trauma. When the inflammatory markers were analysed in combination, those with late childhood trauma also were likely to have an elevated suPAR, CRP and IL-6 inflammatory profile. Collectively, the findings highlight the propensity of late childhood trauma (rather than early or mid-childhood trauma) for the dysregulation of suPAR in early adulthood and support the measurement of suPAR in combination with other markers to better characterise the effects of childhood trauma on adult inflammation. Future studies should use suPAR in combination with CRP and IL-6 to further explore the inflammatory contribution in the relationship between trauma and adverse health outcomes in adulthood.

Rainbow trout (Oncorhynchus mykiss) is an important fish species raised in aquaculture, but it is susceptible to stress, infections diseases. The present study aimed to determine the effects of fulvic acid feed addition on the systemic and mucosal protective mechanisms of juvenile rainbow trout and to elucidate the underlying molecular mechanisms of changes in the gut. Rainbow trout (4.30 ± 0.6 g) diet was supplemented with different levels of fulvic acid: 0% (Control), 0.5%, 1% and 2%. At the end of 8-week feeding trial, growth parameters such as final weight gained weight (%), SGR (F1%) increased, and FCR (all levels) decreased significantly compared to the control group. We found that the activity of lysozyme, glutathione peroxidase, and catalase in the serum were significantly improved, especially after the addition of 0.5% and 1% of fulvic acid. At the same time, the immunoglobulin concentration in the skin mucus was increased with 0.5% supplementation. However, the expression of tnf-α, il-6 and gpx in the intestine was strongly upregulated after supplementation with 2%, indicating oxidative stress and inflammation with this level of fulvic acid inclusion. Furthermore, the mucus lysozyme activity was reduced at this concentration, which can increase the susceptibility to pathogen invasion. The results suggest that adding 0.5%-1% of fulvic acid to the feed of juvenile rainbow trout can help to improve their immune and antioxidative defenses and thereby support the wellbeing of fish.

Osteochondrosis (OC) is a frequent manifestation of developmental orthopaedic disease, and its severe clinical presentation is known as OC dissecans (OCD). OC is defined as a disruption of the endochondral ossification process in the epiphyseal cartilage, and this disease has been reported in different mammalian species, including humans, dogs, pigs, and horses. OCD is an important cause of lameness in sport horses and is a common cause of impaired orthopaedic potential, whose clinical signs may be of minimal magnitude or manifest as severe joint effusion or clinically noticeable lameness. The aetiology of OCD is unknown, although it has traditionally been considered to be multifactorial. In addition to genetic factors, associated factors include both non-genetic elements such as rapid growth, nutrition, trauma, anatomical conformation, and biomechanics. Since the prevalence of the disease varies greatly depending on the horse breed, from 13% in Swedish Warmblood to 53% in Lusitano breed, genetic factors have a great relevance in the appearance and development of OCD in horses. Many genetic modifications have been related, and the genes involved can be grouped into five clusters, related to fundamental functions for the correct development and regeneration of cartilage, such as collagen, laminin, cell signalling, matrix turnover, and transcriptional regulation. Changes in genes such as COL3A1, COL5A1, COL5A2, COL24A1, COL27A1 (collagen cluster), LAMB1 (laminin cluster), PTH, PHT receptors, and IHH (cell signalling), and genes encoding matrix metalloproteinases have been related to the occurrence and severity of diseases in different equine breeds. This review summarises the main factors associated with OC in horses, with particular emphasis on genetic factors.

Since the World Health Organization (WHO) issued guidelines for developing a non-sputum test for active tuberculosis (TB) diagnosis that exhibits similar performance characteristics to sputum-based diagnosis, salivary diagnostic techniques have gained prominence as potential screening tools or adjuncts to existing diagnostics. We searched online databases for studies that looked at salivary diagnostic techniques. Afterwards, duplicates were removed, titles and abstracts were screened, and full-text studies were assessed for eligibility based on inclusion and exclusion criteria. The studies chosen for final analysis underwent a rigorous quality assessment following a QUADAS-2 template, and data were extracted. The primary outcome assessed the difference in mean levels of interleukins between TB+ patients and TB-controls (Hedges' g). We then conducted two subgroup analyses: the first segregated the control group into healthy patients, and those with other respiratory diseases (ORD), and the second addressed three different interleukins separately (IL-6, IL-5, IL-17). The secondary outcome involved comparing salivary molecular diagnostic assays to WHO guidelines. This study is registered with PROSPERO, CRD42024536884. A total of 17 studies, out of an initial 1010, were chosen for the final analysis, but one was then excluded for being of poor quality. Our meta-analyses for the primary outcome revealed minimal diagnostic potential for interleukins. Our first subgroup analysis showed that interleukins were incapable of differentiating active TB patients from both healthy controls and ORD patients. Our second subgroup analysis showed that IL-17 was reduced in active TB patients. Assessment of the secondary outcome revealed that most studies relied on a GeneXpert MTB/RIF assay on saliva, but none fulfilled WHO guidelines for a non-sputum test. Individual biomarkers currently lack sufficient discriminatory power to definitively distinguish active tuberculosis from healthy individuals or those with other respiratory diseases (ORD), reinforcing the need for multi-biomarker panels. Interleukins may be alternatively used as markers for prognosis, severity, or treatment response. Our findings also suggest that assays are unable to meet WHO guidelines.

Aging is often characterized by chronic inflammation, immune system dysregulation, and cellular senescence with chronically elevated levels of pro-inflammatory cytokines. These small glycoproteins are mainly secreted by immune cells, mediating intercellular communication and immune system modulation through inflammatory signaling. Their pro- and anti-inflammatory effects make them a noteworthy research topic as well as a promising ally in combating inflammation and the aging process. Cytokines exert a synergistic role in aging and disease and may prove useful biomarkers of tissue-specific dysregulation, disease diagnosis and monitoring, presenting potential therapeutic options as anti-inflammatory and senolytic medications. In this review, we address the cellular and molecular mechanisms implicating cytokines in the aging process and related diseases, highlighting their biomarker potential. We focus on the current therapeutic strategies, including specific pharmaceutical agents, supplements, a balanced diet, and healthy habits such as exercise, stress management, and caloric restriction.

Interleukins (ILs), a subset of cytokines, play a critical role in the pathogenesis of coronary heart disease (CHD) by mediating inflammation. This review article summarizes the role of ILs such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in the pathogenesis of CHD. Individuals with mild coronary artery disease (CAD) and angina who have ischemic heart disease have higher serum concentrations of IL-1b. Larger studies are needed to verify the safety and assess the effectiveness of low-dose IL-2 as an anti-inflammatory treatment. IL-3 is found more often in patients receiving coronary angioplasty compared to patients with asymptomatic CAD or without CAD. Serum levels of IL-4 are reliable indicators of CAD. An independent correlation between IL-5 and the incidence of CAD was demonstrated. IL-6 helps serve as a reliable biomarker for the degree of CAD, as determined by the Gensini score, and is a key factor in the development of atherosclerosis. Also, variants of IL-7/7R have been linked to the Han Chinese population's genetic susceptibility to CHD. IL-8 plays a role in the progression of CAD occurrences. By interacting with conventional risk factors for CAD, IL-9 may contribute to the development of CAD and offer an innovative approach to its prevention and management. There was a 34% increased risk of a CHD incident for every standard deviation rise in baseline IL-10 levels.

Ovarian endometriomas (OEMs), cystic formations within the ovaries, are a significant manifestation of endometriosis and present in 20-40% of affected women. Despite extensive research, the pathogenesis of endometriosis remains unclear, with retrograde menstruation, coelomic metaplasia, and lymphatic dissemination being proposed mechanisms. OEMs negatively impact ovarian function by reducing the ovarian reserve, disrupting folliculogenesis, and altering the ovarian microenvironment through oxidative stress, inflammation, and fibrosis. Elevated reactive oxygen species (ROS) accelerate follicular atresia, and extracellular matrix remodeling contributes to ovarian damage, while immune dysregulation and cytokine imbalances further exacerbate the condition. The presence of OEMs does not significantly affect live birth rates in in vitro fertilization (IVF) treatments, despite potential reductions in the quality and quantity of oocytes. However, their surgical excision compromises the ovarian reserve. This review highlights the complex mechanisms by which OEMs impair ovarian function and emphasizes the need for further research to develop strategies that mitigate these effects, ultimately improving reproductive outcomes for women with endometriomas.

The incorporation of a functional perfusable microvascular network (MVN) is a common requirement for most organ on-chip-models. Long-term perfusion of MVNs is often required for the maturation of organ phenotypes and disease pathologies and to model the transport of cells and drugs entering organs. In our microphysiological system, we observe that flow can recover perfusion in regressed MVNs and maintain perfusable MVNs for at least 51 days. Throughout the 51 days, however, the MVNs are continuously remodeling to align with the direction of bulk flow and only appear to attain morphological homeostasis with the use of maintenance medium without growth factors. We observed that the flow resistance of the MVNs decreases over time, and using a computational model, we show that stable vessels have higher flow rates and velocities compared to regressing vessels. Cytokine analysis suggests that static conditions generate an inflammatory state, and that continuous flow reduces inflammation over an extended period. Finally, through bulk RNA sequencing we identify that both the endothelial and fibroblast cells are actively engaged in vascular and matrix remodeling due to flow and that these effects persist for at least 2 weeks. This MPS can be applied to study hemodynamically driven processes, such as metastatic dissemination or drug distribution, or to model long-term diseases previously not captured by MPS, such as chronic inflammation or aging-associated diseases.

Space travel is a growing area of interest and includes initiatives such as NASA's Moon-to-Mars Mission. Reports on the cardiovascular effects of space travel reveal changes in morphology, metabolism, and function of the cardiovascular system. In this study, the cardiovascular response to immunization in space was studied in mice which were housed and immunized while on the International Space Station (ISS). Mice were immunized with tetanus toxoid combined with the adjuvant CpG (TT + CpG) and the effects of vaccination in space were studied using transcriptomics. Analysis of the mouse heart transcriptome was performed on flight control and flight-immunized mice. The results show that immunization aboard the ISS stimulates heightened inflammation in the heart via induction of the nuclear factor kappa B (NF-κB) signaling pathway to promote the release of the pro-inflammatory cytokines IFNγ, IL-17 and IL-6. Additional transcriptomic changes included alterations in the cytoskeleton and in the expression of transcripts associated with protection from oxidative stress. In summary, inflammation in the heart can occur following immunization in space. This investigation explores the impact of immune challenges on the heart and lays the groundwork for future research into additional cardiac alterations which can occur during spaceflight.

Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease with characteristic lymphocytic infiltration and fibrosis. Chronic autoimmune changes that occur in the thyroid gland in HT may also affect the lacrimal gland. Objectives: This study aimed to analyze tear biomarkers and explore correlations between these biomarkers and clinical ocular parameters in patients with HT. Methods: A total of 150 participants were divided into three groups: HT (N = 50), non-HT DED (N = 50), and healthy controls (N = 50). The participants underwent a series of diagnostic tests for DED, including the Ocular Surface Disease Index, Tear Break-Up Time, Lid-Parallel Conjunctival Folds, Schirmer test without anesthetic, lissamine green and fluorescein staining. Tear samples were analyzed for cytokine and enzyme levels (interleukin 1β, tumor necrosis factor α, interleukin 6 (IL-6), interleukin 8, interleukin 10 (IL-10), interleukin 17A, matrix metalloproteinase 9 (MMP-9)) using ELISA and multiplex immunoassay. Statistical analyses were conducted to compare groups and assess biomarker correlations. Results: Dry eye disease was observed in more than half of the study group (27/50), with severe symptoms observed in 48.15% of the DED HT subgroup. IL-6 levels were significantly elevated in the DED HT subgroup compared to the non-HT DED group (p = 0.010), suggesting specificity for HT-associated DED. MMP-9 was elevated in both the HT and non-HT DED groups (p < 0.001) but lacked specificity for HT (p = 0.059). The DED HT subgroup exhibited significantly lower IL-10 levels (p = 0.008). Lissamine green staining and LIPCOF were significantly higher in the DED HT subgroup (p < 0.001). Conclusions: Dry eye disease is common in euthyroid HT patients without signs of TAO. This study highlights the potential role of IL-6. Lissamine green staining and LIPCOF are valuable diagnostic tools for assessing the ocular surface in DED HT patients.

Hemophilic arthropathy (HA) is a complication of hemophilia, which is a genetic disorder characterized by a deficiency in blood clotting factors. HA is characterized by joint damage with inflammatory responses, pain, and movement limitations due to recurrent bleeding in the joints. The inflammatory reactions contribute to the activation of coagulation factors, which can exacerbate bleeding and further damage the affected joints. Therefore, the interaction between inflammation and coagulation plays a crucial role in the progression and complications of HA. Management strategies often focus both on inflammation and coagulation to alleviate symptoms and preserve joint function. Temperature can influence the inflammatory response and coagulation. The aim of this work was to understand how temperature management can positively or negatively influence the HA. We have carried out a narrative review of the available literature. This review explores the impacts of temperature on biological processes, and it discusses the possible clinical implications for the HA treatment. Our research shows that cold exposure has anti-inflammatory and analgesic effects, while heat is linked to pro-inflammatory cytokine release. Both hot and cold treatments are ill-advised for hemophilia patients. Heat stimulates neo-angiogenesis, and cold hampers coagulation, posing risks for increased bleeding in individuals with hemophilia.

Cholesterol crystals (CCs) are a key component of atherosclerotic plaques and play a pivotal role in plaque progression, rupture, and the resulting inflammatory responses. CCs emboli trigger proinflammatory cytokines which can potentially lead to organ damage. Spontaneously ruptured aortic plaques (SRAPs) are frequently observed via non-obstructive general angioscopy (NOGA) in patients with or suspected coronary artery disease. The release of CCs from SRAPs can activate the innate immune system and induce neutrophil extracellular trap (NET) formation, further exacerbating inflammation. Inflammation levels in SRAPs vary, and the interleukin (IL)-6 ratio may reflect the degree of inflammation. Systemic inflammation induced by CCs may contribute to conditions that may lead to cerebral infarction, and chronic kidney disease. The effects of anti-inflammatory drugs, including IL-6 inhibitors, IL-1β inhibitors, and colchicine, may be evaluated by measuring the IL-6 ratio in SRAPs. This review examined innate immunity mechanisms associated with CCs in SRAPs sampled via NOGA and discussed their systemic impact and potential therapeutic strategies.

Respiratory diseases are major health concerns worldwide. Chronic respiratory diseases (CRDs) are the third leading cause of death worldwide and some of the most common are chronic obstructive pulmonary disease (COPD), asthma, occupational lung diseases, and pulmonary hypertension. Despite having different etiology and characteristics, these diseases share several features, such as a persistent inflammatory state, chronic oxidative stress, impaired mucociliary clearance, and increased alveolar surface tension. CRDs are not curable; however, various forms of treatment, that help restore airway patency and reduce shortness of breath, can improve daily life for people living with these conditions. In this regard myo-inositol may represent a valid therapeutic adjuvant approach due to its properties. Being a redox balancer, an inflammation modulator, and, most importantly, a component of pulmonary surfactant, it may improve lung function and counteract symptoms associated with respiratory diseases, as recently evidenced in patients with COPD, COVID-19, asthma, and bronchiectasis. The aim of this review is to evaluate the potential therapeutic role of myo-inositol supplementation in the management of patients with respiratory diseases.

Hypertension, a globally prevalent condition, is closely associated with T cell-mediated inflammatory responses. Studies have shown that T cells, by secreting pro-inflammatory cytokines such as interferon-gamma (IFN-γ), Interleukin-17 (IL-17), and Tumor necrosis factor-alpha (TNF-α), directly lead to vascular dysfunction and elevated blood pressure. The activation of Th1 and Th17 cell subsets, along with the dysfunction of regulatory T cells (Tregs), is a critical mechanism in the onset and progression of hypertension. This review explores the role of T cells in the pathophysiology of hypertension and discusses potential therapeutic strategies targeting T cell regulation, such as immunotherapy and gene-editing technologies. These emerging treatments hold promise for providing personalized therapeutic options for hypertensive patients, reducing inflammatory complications, and improving treatment outcomes.

Fatty degenerative osteonecrosis of the jaw (FDOJ) is a chronic, aseptic inflammatory condition that is characterized by molecular disruptions in bone metabolism and necrotic bone marrow within the jawbone cavities. In contrast to the overt clinical signs typically observed in osteopathies, FDOJ frequently presents with a "silent inflammation" phenotype. The electronic databases PubMed, Scopus, and Embase were searched using appropriate search terms, and the methodology was performed according to PRISMA-ScR guidelines. The elevated expression of inflammatory mediators, particularly C-C motif Chemokine Ligand-5/Regulated on Activation, Normal T Cell Expressed and Secreted (CCL5/RANTES), fibroblast growth factor-2, and interleukin-1 receptor antagonist, distinguishes FDOJ at the molecular level and links it to systemic inflammatory and autoimmune diseases. These immunohistochemical markers play a pivotal role in the pathogenesis of chronic inflammation, immune response regulation, and abnormal bone remodeling. Advanced diagnostic tools, such as conebeam computed tomography and trans-alveolar ultrasonography, facilitate the detection of pathological changes that are not easily discernible with conventional radiography. Surgical intervention remains the primary treatment modality, often complemented by therapies that target these molecular pathways to modulate chronic inflammation. This article underscores the importance of integrating molecular diagnostics, advanced imaging, and clinical data for effective FDOJ detection and management.

Background/Objectives: Inflammatory bowel diseases (IBDs) are chronic intestinal disorders with an unpredictable course. In parallel with the advent of new biologic therapies targeting specific interleukin pathways, end-point targets have become more stringent, aiming for mucosal and even histologic healing. Methods: We conducted a prospective study assessing immunohistochemical (IHC) parameters in 46 IBD patients treated with biologic therapy. A similar IHC analysis was performed for comparison with a cohort of 10 "non-IBD" patients. Results: The highest integrated optical density (IOD) of TNF-α was observed in patients with dysplasia, abscesses, mucin depletion and basal plasmacytosis. Non-responders had higher pre- and post-treatment TNF-α expression in both UC and CD compared to responders. On the contrary, the same analysis conducted in the subpopulation treated with anti-TNF-α therapy (Infliximab and Adalimumab) did not reveal a substantial difference in TNF-α expression between responders and non-responders. High pre-treatment interleukin-10 expression was associated with biologic therapy failure, histological inflammatory activity and longer disease duration. Conclusions: Pre-treatment assessment of IL-10 might be a useful tool for identifying a high-risk subset of IBD patients and determining a more aggressive therapy and intensive monitoring strategy.

Hexabromocyclododecane (HBCD) is an environmental contaminant due to its use as a flame retardant in a variety of applications ranging from building insulation, furniture upholstery, and housing for appliances and electronics. HBCD is found in wildlife, human breastmilk, and serum. Interleukin 1-beta (IL-1β) and interleukin 6 (IL-6) are pro-inflammatory cytokines, whose dysregulation is associated with chronic inflammation and the pathologies that result, such as tumor growth, rheumatoid arthritis, Crohn's disease, and multiple sclerosis. HBCD has been shown to increase the secretion of both IL-1β and IL-6 from human immune cells. However, it is not clear if these increases are due solely to HBCD effects on the secretory process or whether it is stimulating cellular production of IL-1β and IL-6. This study examines if HBCD can increase the production of IL-1β and IL-6 by immune cells by simultaneously assessing secreted levels and cellular levels of these cytokines. Additionally, the mechanisms for any observed changes in production are investigated. Peripheral blood mononuclear cells were exposed to HBCD over a range of concentrations and lengths of exposure. HBCD was found to stimulate IL-1β and IL-6 production after 6 hrs. of exposure and production was sustained and intensified at 24 hrs. This increase in IL-1β and IL-6 production appears to, in part, be a result of increased mRNA expression. Additionally, the MAPK pathways, specifically the p38 and p44/42 pathways, appear to be required for HBCD-induced increases in IL-1β and IL-6 production.

Ursolic acid (3-hydroxy-urs-12-ene-28-oic acid, UA) is a pentacyclic triterpene present in numerous plants, fruits and herbs and exhibits various pharmacological effects. However, UA has limited clinical applicability since it is classified as BCS class IV molecule, characterized by low solubility, low oral bioavailability and low permeability. In the present study, UA was isolated from the biomass marc of Lavandula angustifolia and was structurally modified by an induction of indole ring at the C-3 position and amide group at the C-17 position with the aim to enhance its pharmacological potential. This modification resulted in the synthesis of a series of compounds which were investigated for their anti-inflammatory potential both in-vitro and in animal models in comparison to UA. In RAW 264.7 cells, UA and its derivatives were non-cytotoxic up to 10 µM. The derivative UA-1 exhibited a significantly lower IC50 (2.2 ± 0.4 µM) for NO inhibition compared to UA (17.5 ± 2.0 µM). Molecular docking showed strong interactions of UA-1 with TNF-α and NF-κB. UA-1 significantly reduced LPS-induced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in RAW 264.7 macrophages with the inhibition levels of 74.2 ± 2.1 % for TNF-α, 55.9 ± 3.7 % for IL-6 and 59.7 ± 4.2 % for IL-1β at 5.0 µM, respectively and reactive oxygen species while upregulating anti-inflammatory cytokine, IL-10. It also downregulated iNOS, COX-2, p-NF-κB p65, and p-IκBα at both mRNA and protein levels. In LPS-induced systemic inflammation mice model, UA-1 significantly lowered NO, TNF-α, IL-6, IL-1β and serum biochemical parameters, reduced tissue damage, and exhibited improved aqueous solubility and moderate lipophilicity. Overall, UA-1 demonstrated superior anti-inflammatory potential, improved solubility, and better therapeutic potential compared to UA.

Inflammatory processes have been implicated in the pathophysiology of depression. In human studies, inflammation has been shown to act as a critical disease modifier, promoting susceptibility to depression and modulating specific endophenotypes of depression. However, there is scant documentation of how inflammatory processes are associated with neural activity in patients with depression. We therefore tested the hypothesis that the peripheral inflammation markers IL-6 and TNF-α correlate with neural resting state network functional connectivity in depression using functional magnetic resonance imaging (fMRI) and compared it with healthy controls. We used fMRI to investigate the functional connectivity (FC) of the resting state Default Mode Network (DMN) and Salience/Ventral Attention Network (SAL) and their association with the peripheral inflammation markers IL-6 and TNF-α in 25 patients with depression and compared it to 24 healthy subjects. Results of this imaging study revealed that both DMN and SAL resting state networks are differentially associated with distinct immunological pathways depending on whether a person has a depressive phenotype or is healthy. While the DMN FC correlated with the concentration of the cytokine IL-6 in healthy subjects, SAL FC's connectivity correlated with the cytokine TNF-α's concentration. This study highlights the importance of peripheral inflammatory processes in depression and suggests a modulatory effect on neural resting state networks depending on the state of depression.

Chronic muscle fatigue is a condition characterized by debilitating muscle weakness and pain. Based on our recent finding to study the potential effect of mTOR on ATG13 inactivation in chronic muscle fatigue, we report that biweekly oral administration with MHY1485, a potent inducer of mTOR, develops chronic illness in mice resulting in severe muscle weakness. As a mechanism, we observed that MHY1485 feeding impaired ATG13-dependent autophagy, caused the infiltration of inflammatory M1 macrophages (Mφ), upregulated IL6 and RANTES by STAT3 activation, and augmented demyelination in muscle-serving nerve fibers. Interestingly, these mice displayed worsened muscle fatigue during 2-day post-treadmill exercise, suggesting the critical role of chronic mTOR activation in potential PEM pathogenesis. Interestingly, ATG13-repressor mice exhibited enhanced infiltration of M1Mφ cells, STAT3 activation, demyelination of nerve fibers, and PEM-like symptoms, suggesting the potential role of ATG13 impairment in post-exertional fatigue. HIGHLIGHTS: The potential role of mTOR activation in post-exertional fatigue is highlighted. As a molecular mechanism, mTOR activation augments autophagy impairment via ATG13 inactivation. Autophagy impairment induces IL-6 and RANTES via STAT3, demyelinates nerves in the muscle and spinal cord. ATG13 repressor mice (Tg-ATG13) displayed inflammatory demyelination and post-treadmill fatigue.

Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of genetic disorders affecting the development and function of the immune system. While IEIs traditionally present with recurrent infections, an increasing number of cases manifest with early-onset severe atopy, including atopic dermatitis, food allergies, asthma, and allergic rhinitis-features that are often overlooked. This can lead to delayed diagnosis and treatment, which is crucial for IEI patients due to the risk of severe infections. We conducted a literature search and reviewed all IEIs that can present with early-onset severe atopy. The hallmark features of these disorders often include early-onset, persistent, and severe atopic dermatitis, food allergies, and recurrent episodes of asthma, which may be refractory to treatments. Additionally, we discuss the importance of recognizing such severe atopy as a potential indicator of an underlying immune deficiency, particularly when accompanied by unusual infections, growth failure, or autoimmunity. This review aims to raise awareness of this association and emphasize the need for early diagnosis and genetic testing in patients with atypical or treatment-resistant allergic diseases, allowing for more timely diagnosis of underlying immunodeficiencies and appropriate treatments.

The 1,2,3-triazole-based chemosensors, synthesized through Cu(I)-catalyzed azide-alkyne cycloaddition via 'click chemistry', offer a straightforward yet highly effective method for detecting metal cations and anions with remarkable accuracy, selectivity and sensitivity, making them invaluable across various fields such as chemistry, pharmacology, environmental science and biology. The selective recognition of these ions is crucial due to their significant roles in biological and physiological processes, where even slight concentration variations can have major consequences. The article reviews literature from 2017 to 2024, highlighting advancements in the synthesis of 1,2,3-triazole-based ligands and their application (along with sensing mechanism) for detection of various ions causing health and environmental hazards. The detection aspects have been discussed sequentially for the transition-, inner transition-, and the metals from the s or p block of the periodic table.

Acute myeloid leukemia (AML) is a deadly form of leukemia with ineffective traditional treatment and frequent chemoresistance-associated relapse. Personalized drug screening holds promise in identifying optimal regimen, nevertheless, primary AML cells undergo spontaneous apoptosis during cultures, invalidating the drug screening results. Here, we reconstitute a 3D osteogenic niche (3DON) mimicking that in bone marrow to support primary AML cell survival and phenotype maintenance in cultures. Specifically, 3DON derived from osteogenically differentiated mesenchymal stem cells (MSC) from healthy and AML donors are co-cultured with primary AML cells. The AML cells under the AML_3DON niche showed enhanced viability, reduced apoptosis and maintained CD33+ CD34-phenotype, associating with elevated secretion of anti-apoptotic cytokines in the AML_3DON niche. Moreover, AML cells under the AML_3DON niche exhibited low sensitivity to two FDA-approved chemotherapeutic drugs, further suggesting the physiological resemblance of the AML_3DON niche. Most interestingly, AML cells co-cultured with the healthy_3DON niche are highly sensitive to the same sample drugs. This study demonstrates the differential responses of AML cells towards leukemic and healthy bone marrow niches, suggesting the impact of native cancer cell niche in drug screening, and the potential of re-engineering healthy bone marrow niche in AML patients as chemotherapeutic adjuvants overcoming chemoresistance, respectively.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare but debilitating autoimmune disease of the central nervous system (CNS) for which several biotherapies have recently been approved on the market. Historically, NMOSD disease-modifying treatments relied on wide-spectrum off-label immunosuppressants, such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Since 2015, evidence has accumulated to support off-label biotherapies (rituximab and tocilizumab) and to approve satralizumab, inebilizumab, eculizumab, and ravulizumab. This next generation of drugs provides several targeted disease-modifying treatment options for NMOSD. Here, we review this modern panel. We first review the mechanistic rationales associated with their specific targets. We then review the pivotal evidence supporting their use in practice and their respective regimens. Lastly, we discuss the positioning of each therapeutic class. The current therapeutic options in NMOSD comprise three targeted mechanisms at different stages of a unique tissue-injury cascade: B-cell depleting, anti-cytokine, and anti-complement therapies. One drug has been approved on the market in each class. The current consensus proposes positioning the approved drugs as first-line treatments for newly-diagnosed patients and as alternative therapies in case of failure of historical treatment. Yet, there has been limited acceptance in practice due to high drug prices.

The aim of the present research is to investigate anti-UVB radiation activity of total flavonoids from Ilex latifolia Thunb. (namely large-leaved Kuding tea) on human keratinocyte cell line (HaCaT cells) based on network pharmacology and molecular docking technique. Network pharmacology was used to screen target genes of active ingredients from Ilex latifolia Thunb. associated with UVB irradiation. The possible signaling pathways were analyzed by KEGG enrichment and verified by cellular experiments. Molecular docking was used to assess the affinity between the active ingredients and the core targets. The prediction of network pharmacology and molecular docking was identified by series experiment in UVB-irradiated HaCaT cells. Network pharmacology results showed that the active ingredients of Ilex latifolia Thunb. for anti-UVB irradiation were mainly flavonoids, and the possible signaling pathways were involved in PI3K-AKT, apoptosis, MAPKs, NF-κB, and JAK-STAT3. Molecular docking indicated key binding activity between AKT1-Glycitein, STAT3-Formononetin, CASP3-Formononetin, TNF-Kaempferol, CASP3-Luteolin, and AKT1-Quercetin. The total flavonoid pretreatment (0.25-1.0 mg/mL) down-regulated the expression of IL-6, IL-1β, and TNF-α in the cells determined by ELISA. The expression of phosphor PI3K, phosphor AKT, phosphor JAK, phosphor STAT3, phosphor JNK, and phosphor p38 MAPKs and COX-2 proteins in cytosolic and NF-κB p65 protein in nucleus were down-regulated and determined by western blot. It also protected UVB-irradiated cells from apoptosis by reducing apoptosis rate and down-regulating active-caspase 3. In a word, the total flavonoid treatment protected HaCaT cells from UVB injuries effectively, and the potential mechanism involves PI3K-AKT, JAK-STAT3, MAPK, and NF-κB pathway by anti-inflammatory and apoptosis action in cells. The mechanism in vivo experiment needs to be further confirmed in future.

This study aimed to assess the influence of different types of blue light sources on male and female rats' puberty onset, the morphologic-induced alterations in reproductive organs tissues, the impact on inflammation and oxidative stress markers, anxiety levels, and mathematical modeling for tissue data interpretation. Four groups of sixteen rats each (8 females and 8 males/group) were investigated: three groups were exposed to blue light from mobile phones (MP), computer screens (PC), or LED lamps (LED) versus the control group (CTRL). The rats in the CTRL group had no exposure while the other groups were exposed for 30 days to the blue light of MP, PC, and LED for 16 h per day. Serum levels of cortisol, TNF-α, IL-6, and MMP-2 and MMP-9 ovaries and testis tissue levels were analyzed using the ELISA technique. Total oxidative stress (TOS), nitric oxide (NO), and malondialdehyde (MDA) in serum were determined spectrophotometrically. Histomorphological examination was performed on both male and female genital organs. Rats of both sexes presented significant early onset of puberty secondary to blue light exposure. LED-emitted light significantly increased TNF-α and MMP-9 levels in both sexes. The MP and PC emitted light significantly affected the levels of MMP-2 in both females and males. Levels of TOS and NO were increased by LED, respectively by MP and LED exposure in female rats. The histopathological examination revealed no statistically significant differences in the ovaries and testes of rats across the different groups. Blue light exposure induces precocious puberty, by accelerating sexual maturation, and triggers the overproduction of MMPs that could promote organic alteration through tissue remodeling. Oxidative stress parameters were upregulated only in female rats, while cortisol levels were higher in male rats.

Chromium has been recognized for its beneficial effects on inflammation reduction; therefore, we conducted a systematic review and meta-analysis to find the effect of chromium supplementation on serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in subjects aged 18 years and older. Related articles were identified by searching databases such as the Cochrane Library, ClinicalTrials.gov, ISI Web of Science, Scopus, and PubMed up until Agust 2024. We computed the mean differences (MD) along with their standard deviations (SDs) to carry out the meta-analysis. Statistical heterogeneity of the intervention effects was assessed using I-squared statistics and Cochran's Q test. In total, twelve and eleven studies were included in the present systematic review and meta-analysis, respectively. The pooled results indicated that the differences in serum levels of CRP and TNF-α between chromium group and the comparison group were statistically significant (CRP: weighted mean difference (WMD) = -0.58 mg/L; 95% confidence interval (CI) = -0.95, -0.22 mg/L; P = 0.002; TNF-α: WMD = -1.22 pg/ml; 95% CI = -1.91, -0.53 pg/ml; p = 0.001). In contrast, chromium supplementation resulted in a non-significant decrease in serum levels of IL-6 (WMD = -0.63 pg/ml; 95% CI: -1.67, 0.4 pg/ml; P < 0.001). Our study supports the beneficial effect of chromium supplementation on serum concentration of CRP and TNF-α, but our results showed that chromium supplementation non-significantly reduced the serum levels of IL-6. However, it seems that chromium formulation, participants' BMI, sample size, and geographical region are strong variables that predict the effect of chromium supplementation on inflammatory mediators.

Purpose: To report a case of cystoid macular edema (CME) secondary to immune recovery uveitis (IRU) in a patient with previous history of cytomegalovirus (CMV) retinitis and leukemia, which was successfully treated with tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist. Method: The clinical records of the case were reviewed, focusing on demographics, image findings, and clinical course. Results: A 17-year-old female with a past medical history of T-cell acute lymphoblastic leukemia (T-ALL) undergoing chemotherapy for two years presented with active CMV retinitis. She was successfully treated with intravitreal foscarnet injections and systemic ganciclovir. After 5 months of systemic valganciclovir maintenance and following cessation of chemotherapy, the patient developed bilateral CME and vasculitis, and was diagnosed with IRU. CME management was challenging due to a history of bilateral avascular necrosis of the femoral head resulting from prolonged systemic corticosteroid use. Two cycles of monthly TCZ infusions were administered at the dosage of 8mg/kg. Subsequently, the CME and retinal vasculitis resolved significantly without any evidence of inflammation in the anterior chamber and vitreous. Conclusion: The index case report demonstrated the safety and efficacy of the IL-6 receptor antagonist TCZ in treating CME associated with IRU in a non-HIV CMV retinitis patient.

Originally discovered in the 1890s, the complement system has traditionally been viewed as a "compliment" to the body's innate and adaptive immune response. However, emerging data have shown that the complement system is a much more complex mechanism within the body involved in regulating inflammation, gene transcription, attraction of macrophages, and many more processes. Sustained complement activation contributes to autoimmunity and chronic inflammation. Pulmonary hypertension is a disease with a poor prognosis and an average life expectancy of 2-3 years that leads to vascular remodeling of the pulmonary arteries; the pulmonary arteries are essential to host homeostasis, as they divert deoxygenated blood from the right ventricle of the heart to the lungs for gas exchange. This review focuses on direct links between the complement system's involvement in pulmonary hypertension, along with autoimmune conditions, and the reliance on the complement system for vascular remodeling processes of the pulmonary artery. Furthermore, circadian rhythmicity is highlighted as the disrupted homeostatic mechanism in the inflammatory consequences in the vascular remodeling within the pulmonary arteries, which could potentially open new therapeutic cues. The current treatment options for pulmonary hypertension are discussed with clinical trials using complement inhibitors and potential therapeutic targets that impact immune cell functions and complement activation, which could alleviate symptoms and block the progression of the disease. Further research on complement's involvement in interstitial lung diseases and pulmonary hypertension could prove beneficial for our understanding of these various diseases and potential treatment options to prevent vascular remodeling of the pulmonary arteries.

We demonstrate an organic electrochemical transistor (OECT) biosensor for the detection of interleukin 6 (IL6), an important biomarker associated with various pathological processes, including chronic inflammation, inflammaging, cancer, and severe COVID-19 infection. The biosensor is functionalized with oligonucleotide aptamers engineered to bind specifically IL6. We developed an easy functionalization strategy based on gold nanoparticles deposited onto a poly(3,4-ethylenedioxythiophene) doped with polystyrenesulfonate (PEDOT:PSS) gate electrode for the subsequent electrodeposition of thiolated aptamers. During this functionalization step, the reduction of sulfide bonds allows for simultaneous deposition of a blocking agent. A detection range from picomolar to nanomolar concentrations for IL6 was achieved, and the selectivity of the device was assessed against Tumor Necrosis Factor (TNF), another cytokine involved in the inflammatory processes.

Digital dermatitis (DD) poses a major animal welfare concern for the dairy industry, with even broader economic implications for the agricultural industry worldwide. The postbiotic, a Saccharomyces cerevisiae fermentation product (SCFP), has had a positive influence on the innate immune system of cattle, which makes it a potential candidate as a feed supplement as part of a prevention strategy for DD. This study investigated the effect of a commercial SCFP feed supplement compared to a control feed supplement on the production of pro-inflammatory cytokines (IL-1β and IL-6) by peripheral blood mononuclear cells (PBMCs) in Holstein Friesian steers experimentally infected with DD. The results showed that SCFP supplementation was associated with an overall reduced IL-1β production (p = 0.005), particularly prior to experimental inoculation with a DD lesion homogenate. However, the results of the analysis suggest that the innate immune system in the SCFP group became prepared to respond more rapidly to DD infection post-inoculation. During active (M2), chronic (M4), and focal flare-ups (M4.1) of DD, SCFP supplementation resulted in a more rapid secretion of IL-1β (M2: p = 0.038; M4/M4/1: p = 0.034). A more rapid response to DD infection for IL-6 was only found for chronic (M4) and focal flare-ups (M4.1) of DD (p = 0.006). These findings emphasize the difference in cytokine response between various stages of DD in the SCFP group compared to the control, highlighting implications for DD prevention and treatment.

Recent advances in fate mapping and single-cell technologies have revealed how the dynamics and function of tissue-resident macrophages are shaped by their environment. However, macrophages in sensory organs such as the cochlea where the central nervous system and peripheral nervous system meet remain understudied. Combining single-cell transcriptomics, fate mapping, and parabiosis experiments, we show that five types of myeloid cells including three tissue-resident macrophage subpopulations, coexist in the mouse cochlea. The three macrophage subsets showed different potential functions in relationship with their specific topography across cochlear compartments. Further analysis revealed that they were partially derived from yolk sac progenitors during development, while in adulthood, most cochlear macrophages were long-term resident. Finally, we showed that cochlear macrophage morphology and density changed during aging. Our findings show that cochlea is a microenvironment with a unique heterogeneity of macrophages in terms of gene expression, spatial distribution, ontogeny, and function.

Osteopontin (OPN) is a pro-inflammatory protein that influences bone remodelling, wound healing, angiogenesis, allergic inflammation, and skin diseases such as psoriasis, contact dermatitis and skin cancer. However, the role of OPN in the skin remains unclear. Therefore, this study aimed to investigate the role of OPN in the skin, particularly in the context of ultraviolet (UV) irradiation-induced inflammation. OPN expression and its effects on inflammatory modulators were assessed in human skin, in a mouse model and in vitro, using a UV source emitting both UVB and UVA radiation, which collectively contribute to UV-induced skin inflammation. OPN expression increased in human and mouse skin after UV irradiation. Compared with wild-type mice, UV irradiation-induced skin phenotypes, such as erythema and skin thickening, were alleviated in OPN-/- mice. In addition, the number of immune cells recruited to the skin after UV irradiation and the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) were observed to be decreased in the skin of OPN-/- mice compared with that of wild-type mice. By contrast, the degree of skin inflammation was higher in the hOPN KI mice than in wild-type mice. Treatment with recombinant OPN increased the expression of MMP-1 and inflammatory cytokines in human dermal fibroblasts and epidermal keratinocytes in vitro. Our results suggest that OPN may play a regulatory role in UV-induced skin inflammation.