Inflammatory Cytokine Response Research Articles

Siglec-E augments adipose tissue inflammation by modulating TRAF3 signaling and monocytic myeloid-derived suppressor cells during obesity

BackgroundObesity is associated with dysregulated metabolism and low-grade chronic inflammation in adipose tissue (AT). Immune cells, including macrophages, T cells, and neutrophils, infiltrate the AT and secrete proinflammatory cytokines to exacerbate the AT inflammation. RNA-Seq analysis of AT immune cells isolated from mice fed a high-fat diet (HFD) versus normal fat diet (ND) identified a panel of genes that were markedly downregulated, including sialic acid-binding Ig-like lectin E (siglec-E), in HFD compared to ND mice.MethodsA series of experiments in wild-type (WT) and siglec-E knockout (siglec-E KO) mice was designed to investigate the effect of HFD on the functional role of siglec-E in the regulation of AT inflammation and adipogenesis. We analyzed the changes in immune phenotypes, inflammatory response, adipogenesis, and levels of cytokines and chemokines after HFD and ND feeding.ResultsHFD consumption significantly increased the body weight and blood glucose levels in siglec-E KO mice relative to those of WT mice. This was associated with an increased infiltration of macrophages, CXCR3 expressing CD8 T cells, and monocytic myeloid-derived suppressor cells (M-MDSCs) with a concomitant decrease in numbers of dendritic cells (DCs), in the AT of siglec-E KO fed HFD versus the WT HFD counterparts. The HFD-fed siglec-E KO mice also exhibited elevated expression of intracellular Akt and TNF receptor-associated factor 3 (TRAF3) signaling, inducing C/EBPα, FASN, PPARγ, and resistin in suprascapular AT compared to WT HFD-fed mice. Taken together, these results suggest that a genetic deficiency of siglec-E plays a key role in inducing AT inflammation by differentially altering M-MDSCs and CD8+CXCR3+ T cell function and adipogenesis by TRAF3 and Akt signaling in AT.ConclusionOur findings strongly suggest that modulation of siglec-E pathways might have a protective effect at least in part against AT inflammation and metabolic disorders.

Integrated Transcriptome Analysis Reveals the Lung miRNA–mRNA Regulatory Network Associated with Avian Pathogenic E. coli Infection

Avian pathogenic E. coli (APEC), one of the most common pathogens, can cause localized or systemic infections and lead to significant economic losses in the poultry industry annually. Recently, evidence suggests that microRNAs (miRNAs) play important roles in the host immune response to bacterial infection by targeting mRNAs. However, few studies have examined the immune mechanisms of miRNAs and mRNAs in chicken lungs following APEC infection. Herein, hematoxylin–eosin staining and qRT-PCR were employed to investigate APEC-induced lung inflammation in chickens. RNAseq was used to identify the miRNAs and mRNAs expression profile between the APEC infection group (APEC) vs. the Control group (Control). The results show that APEC can induce lung lesions in chickens and increase the expression levels of inflammatory cytokines (IL1β, IL8, IL6, and TNFα). High-quality sequencing data were obtained, of which more than 93% of the reads can be mapped to the chicken genome. A total of 22 differentially expressed (DE) miRNAs and 608 DE mRNAs were detected in the APEC vs. the Control. Remarkably, 23 regulatory pairs of miRNA–mRNA interactions were identified in chicken lungs upon APEC infection. Further validation revealed that gga-miR-214 could directly target the RAB37 gene upon APEC infection to modulate the expression of inflammatory cytokine response. This study provides new insights into the host immune response to APEC infection.

Differentially Expressed Genes in Cardiomyocytes of the First Camelized Mouse Model, Nrapc.255ins78 Mouse

Background/Objectives: The first camelized mouse model (Nrapc.255ins78) was developed to investigate the mechanisms underlying camels’ adaptation to extreme environments. Previous studies demonstrated that these mice exhibit a cold-resistant phenotype, characterized by increased expression of inflammatory cytokine-related genes in the heart under cold stress. Nebulin-related anchoring protein (NRAP) plays a critical role in organizing myofibrils during cardiomyocyte development. This study builds on prior research by analyzing the heart transcriptomes of Nrapc.255ins78 mice under non-stress conditions to explore the origins of inflammatory cytokine responses during cold exposure. Methods: RNA sequencing was performed on the hearts of 12-week-old male and female Nrapc.255ins78 and wild-type control mice. Results: Differential expression analysis identified 25 genes, including 12 associated with cell cycle and division, all consistently downregulated in Nrapc.255ins78. Notably, the calcium and integrin-binding protein gene (Cib3) was significantly upregulated (FDR < 0.05; p < 0.001). Conclusions: These differentially expressed genes suggest altered calcium dynamics in cardiomyocytes and mechanisms for maintaining homeostasis, supporting the hypothesis that inflammatory cytokines during cold exposure may represent an adaptive response. These findings provide valuable insights into the genetic mechanisms of temperature adaptation in camels and highlight potential pathways for enhancing stress resistance in other mammals.

TET2-loss enhances immediate and time-resolved IFNγ signaling responses across myeloid differentiation.

Signaling responses to cytokines are disrupted in clonal hematopoiesis and myeloid malignancies. To better identify specific signaling response alterations in the presence or absence of TET2, we developed a 36-parameter CyTOF panel of both surface marker and phosphoprotein antigens in murine BM. We show diverse, cell-type specific inflammatory cytokine responses in healthy hematopoietic cells. We next investigated changes associated with bone marrow cells from Tet2KO mice. High dimensional surface marker phenotyping revealed expansion of HSPCs, committed cKIT+Ly6C+ myeloid progenitors, and monocytes. Loss of TET2 function increased the magnitude of response to extracellular perturbations, including IFNγ and H2O2. Response time courses revealed that IFNγ-mediated pSTAT1 remains elevated over time in Tet2KO. Further, IFNγ resulted in a more significant increase in major histocompatibility complex class II (MHCII) expression in Tet2KO immortalized progenitor cells than in Tet2WT. Inhibition of Janus kinase 1 and 2 (JAK1/2) with ruxolitinib significantly reduced STAT1 phosphorylation and MHCII expression in Tet2KO cells. Our results identify targetable disrupted signaling responses in Tet2KO cells.

Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells.

Organs of the gastrointestinal tract contain tissue-resident immune cells that function during tissue development, homeostasis, and disease. However, most published human organoid model systems lack resident immune cells, thus limiting their potential as disease avatars. For example, human intestinal organoids (HIOs) derived from pluripotent stem cells contain epithelial and various mesenchymal cell types but lack immune cells. In this study, we aimed to develop an HIO model with functional tissue-resident macrophages. HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined invitro. Following 2 weeks of coculture, the organoids were used for transcriptional profiling, functional analysis of macrophages, or transplanted into immunocompromised mice and matured invivo for an additional 10-12 weeks. Macrophages were incorporated into developing HIOs and persisted for 2 weeks invitro HIOs and for at least 12 weeks in HIOs invivo. These cocultured macrophages had a transcriptional signature that resembled those in the human fetal intestine, indicating that they were acquiring the features of tissue-resident macrophages. HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10. We generated an HIO system containing functional tissue-resident macrophages for an extended period. This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease.

Extracellular vesicles in dry eye disease and Sjögren's syndrome: A systematic review on their diagnostic and therapeutic role.

Extracellular vesicles (EVs), defined as membrane-bound vesicles released from all cells, are being explored for their diagnostic and therapeutic role in dry eye disease (DED). We systematically shortlisted 32 articles on the role of EVs in diagnosing and treating DED. We cover the progress in the last 2 decades on the classification and isolation of EVs and their role in DED. The diagnostic predictability of exosomes was evaluated in Sjögren syndrome (SS) patients' tears, plasma, and saliva, where upregulation of inflammatory proteins was reported uniformly across studies. Also, we evaluate the therapeutic effects of MSC-derived EVs in in vitro and in vivo studies of SS and DED mouse models. A significant response occurs at a functional level with improved tear production and saliva flow rate and at a cellular level with reduced lymphocyte infiltration, improved corneal structural integrity, decreased epithelial cell apoptosis, and dampening of the inflammatory cytokine response. The proposed mechanisms of EV action include PD-L1, PRDM, NLRP-3, and Nf-kb pathways, and an increase in M2 macrophage phenotype. Current use of exosomes in DED is limited due to their cumbersome isolation techniqus. Further research on human subjects is needed, in addition to optimizing exosome isolation and delivery methods.

Inflammatory Cytokine Response in Dengue Infected Female of Reproductive Age: Insight with Reference to a Pregnant Case

Dengue treatment and management is challenging during the epidemic especially among the risk groups and to mitigate the risks becomes even more complicated in absence of specific medicine and vaccines. Till date, there are no specific research endeavours in Nepal focusing on pregnant women with dengue and there is evident gap in research concerning the treatment of pregnant women due to overlapping clinical and hematological manifestations with physiological changes of gestation. The study comprises clinically diagnosed one dengue positive pregnant female, five female patients with dengue in Sukraraj Tropical and Infectious Disease Hospital (STIDH), Kathmandu and five healthy volunteers of same reproductive age. The study investigates six different inflammatory cytokines; IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF levels in plasma and were quantified using Cytometric Bead Array. The Cytokine profiles and blood parameters were statistically analyzed using confidence intervals of 93.75% as permitted by sample size and visualized with box and whisker plot with a highlighted pregnant case. The study shows IL-6 and IL-10 levels are elevated on dengue cases as compared to healthy while TNF and IL-12p70 levels are elevated exceeding the upper limit of the acute dengue cases in the pregnant subject, underscoring heightened inflammatory activity during synchronous pregnancy and dengue infection. There were significant reductions in hemoglobin and leukocyte counts in the pregnant dengue case compared to non-pregnant. These findings suggest cytokine modulations occur during pregnancy and underscores the importance of these patterns provide insight into targeted therapeutic and diagnostic strategies to mitigate the risks for vulnerable population.

Cytokine and Chemokine Responses of Peripheral Blood Mononuclear Cells from Dogs Infected with Mycobacterium bovis.

Mycobacterial infections are an important emerging zoonosis in companion animals for which diagnostic options remain imperfect, and the canine immunological response to these infections has been poorly investigated. We sought to further define the cellular response of peripheral blood mononuclear cells (PBMCs) from dogs infected with Mycobacterium bovis, as determined using a commercial interferon-gamma response assay (IGRA). To this end, PBMCs from healthy or infected dogs were collected. Serum samples were tested to further classify dogs as seropositive or seronegative for circulating antibodies against M. bovis using the DPP® VetTB Assay, Idexx M. bovis antibody ELISA, and a novel purified protein derivative ELISA. Isolated PBMCs were stimulated with mycobacterial proteins (PPDB or ESAT-6/CFP-10), and 13 cytokines/chemokines were measured in the supernatant. These concentrations were determined using the CYTOMAG-90K MILLIPLEX MAP Canine Cytokine/Chemokine system. PBMCs from infected dogs released IFN-γ in response to stimulation, but this response was reduced in those that had seroconverted. Similarly, cells stimulated with PPDB secreted increased amounts of TNF-α when dogs were seronegative, but cells taken from seropositive dogs did not. Finally, the IL-18 response of seropositive dogs was reduced compared to those that were seronegative in response to PPDB, potentially suggesting that these dogs have a reduced macrophage functionality. This work demonstrates that the inflammatory cytokine response may wane following seroconversion with deleterious consequences for the host response. Overall, combining IFN-γ and TNF-α assessment during diagnosis may increase IGRA sensitivity, whilst further work is needed to better understand the prognostic and diagnostic implications of seroconversion in dogs.

Comparison of inflammatory mediator cytokine responses to inactivated virus platform COVID-19 vaccines between elderly and young adult populations.

The coronavirus disease 2019 (COVID-19) pandemic has encouraged global vaccine research, yet vaccine effectiveness in the elderly remains a concern due to immunosenescence. The aim of this study was to compare the cytokine response elicited by an inactivated virus-based COVID-19 vaccine between elderly and young adults, focusing on key cytokines involved in cellular and humoral immunity: tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2, IL-6, IL-10, and interferon-gamma (IFN-γ). A cross-sectional study was conducted in the Jakarta-Bogor region of Indonesia from January 2023 to December 2023. The study population was divided into two age cohorts: elderly (60-85 years) and younger adults (30-40 years). Blood samples were collected twice, after the first booster dose and four weeks after the second booster dose. Serum cytokine concentrations were measured using Luminex assays with microparticles conjugated to monoclonal antibodies against TNF-α, IL-2, IL-6, IL-10, and IFN-γ. Comparisons of the cytokine levels were conducted using Student's t-tests or Mann- Whitney U tests as appropriate. A total of 74 individuals were included, with 37 each in the elderly and young adult groups. The results showed significant differences in cytokine responses between the two age groups. After the first booster, the levels of IL-6 and IFN- γ were significantly higher in young adults compared to the elderly. After the second booster, the levels of IL-6 were still significantly higher in the young adult group compared to the elderly group (p = 0.001). Data indicated that after the second booster dose, the levels of TNF-α increased significantly in the young adult group only (p = 0.004), while the levels of IL-2 (p = 0.040) and IFN-γ (p = 0.006) increased in the elderly group only compared to after the first dose. IL-10 levels increased in both groups (both had p = 0.020). This study highlights that young adults had stronger pro-inflammatory responses, while the elderly relied more on IL-2 and IFN-γ for T-cell immunity, suggesting the need for vaccination strategies for the elderly to optimize immune responses.

IL-1β-induced pericyte dysfunction with a secretory phenotype exacerbates retinal microenvironment inflammation via Hes1/STAT3 signaling pathway

Retinal pericytes are mural cells surrounding capillaries to maintain the integrity of blood-retina barrier and regulate vascular behaviors. Pericyte loss has been considered as the hallmark of diabetic retinopathy (DR), which is a major complication of diabetes and the leading cause of blindness in adults. However, the precise function of pericytes in regulating the retinal microenvironment and the underlying mechanism remains largely unknown. In this study, we observed a secretory phenotype of pericytes with elevated inflammatory cytokines in response to Interleukin-1β (IL-1β), a canonical inflammatory cytokine which significantly increases during the initial stages of diabetic retinopathy. This phenotype is also accompanied by reduced expression of adherent junction proteins and contractile proteins. Paracrine cytokines derived from pericytes further induce the chemotaxis of microglia cells and trigger detrimental changes in endothelial cells, including reduced expression of tight junction protein Occludin and increased apoptosis. Mechanically, the secretion potential in pericytes is partially mediated by Hes1/STAT3 signaling pathway. Moreover, co-injection of stattic, an inhibitor targeting STAT3 activation, could effectively attenuate IL-1β-induced retinal inflammation and microglial activation in retina tissues. Collectively, these findings demonstrate the potential of retinal pericytes as an initial inflammatory sensor prior to their anatomical pathological loss, via undergoing phenotypic changes and secreting paracrine factors to amplify local inflammation and damage endothelial cells in vitro. Furthermore, inhibition of STAT3 activation by inhibitors significantly ameliorates IL-1β-induced retinal inflammation, suggesting STAT3 in retinal pericytes as a promising target for alleviating DR and other IL-1β-induced ocular diseases.

Chronic inflammation deters natural killer cell fitness and cytotoxicity in myeloid leukemia

AbstractNatural killer (NK) cells play an integral role in immunosurveillance against myeloid malignancies, with their mature phenotype and abundance linked to prolonged treatment-free remission in chronic myeloid leukemia (CML). However, NK cell function is suppressed during the disease, and the orchestrators of this impairment are not fully understood. Using a chimeric BCR::ABL1+ CML mouse model, we characterized the impact of the leukemic microenvironment on NK cell function. We showed that NK cells have reduced counts, immature phenotype, poor cytotoxicity, and altered expression of activating and inhibitory receptors in CML mice, which revert to a steady state upon BCR::ABL1 inhibition. Single-cell RNA sequencing revealed an inflammatory cytokine response in CML-exposed NK cells, highlighted by the tumor necrosis factor α (TNFα)-induced gene signature, upregulation of TNFα receptor 2, and enrichment of SOCS family genes such as Cish, the critical NK cell checkpoint. Ex vivo exposure of healthy NK cells to leukemic soluble factors compromised target-specific NK cell degranulation, which was partially rescued by targeting Cish or TNFα. In alignment with these findings, NK cells from healthy donors displayed suppressed cytotoxicity when exposed to plasma from untreated patients with CML, with a partial restoration upon Cish or TNFα inhibition. Furthermore, NK cells from newly diagnosed patients with CML predestined for blast crisis showed an enrichment of the TNFα-induced proinflammatory gene signature identified in CML mice. These results suggest that targeting inflammatory signaling could enhance NK cell-based immunotherapies for CML.

Differential TLR-ERK1/2 Activity Promotes Viral ssRNA and dsRNA Mimic-Induced Dysregulated Immunity in Macrophages.

RNA virus-induced excessive inflammation and impaired antiviral interferon (IFN-I) responses are associated with severe disease. This innate immune response, also referred to as "dysregulated immunity" is caused by viral single-stranded RNA (ssRNA)- and double-stranded-RNA (dsRNA)-mediated exuberant inflammation and viral protein-induced IFN antagonism. However, key host factors and the underlying mechanism driving viral RNA-mediated dysregulated immunity are poorly defined. Here, using viral ssRNA and dsRNA mimics, which activate toll-like receptor 7 (TLR7) and TLR3, respectively, we evaluated the role of viral RNAs in causing dysregulated immunity. We observed that murine bone marrow-derived macrophages (BMDMs), when stimulated with TLR3 and TLR7 agonists, induced differential inflammatory and antiviral cytokine response. TLR7 activation triggered a robust inflammatory cytokine/chemokine induction compared to TLR3 activation, whereas TLR3 stimulation induced significantly increased IFN/IFN stimulated gene (ISG) response relative to TLR7 activation. To define the mechanistic basis for dysregulated immunity, we examined cell-surface and endosomal TLR levels and downstream mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kB) activation. We identified significantly higher cell-surface and endosomal TLR7 levels compared to TLR3, which were associated with early and robust MAPK (p-ERK1/2, p-P38, and p-JNK) and NF-kB activation in TLR7-stimulated macrophages. Furthermore, blocking EKR1/2 and NF-kB activity reduced TLR3/7-induced inflammatory cytokine/chemokine levels, whereas only ERK1/2 inhibition enhanced viral RNA mimic-induced IFN/ISG responses. Collectively, our results illustrate that high cell-surface and endosomal TLR7 expression and robust ERK1/2 activation drive viral ssRNA mimic-induced excessive inflammatory and reduced IFN/ISG response and blocking ERK1/2 activity would likely mitigate viral-RNA/TLR-induced dysregulated immunity.

VCPIP1 negatively regulates NF-κB signaling pathways by deubiquitinating and stabilizing Erbin in MDP-stimulated macrophages

Macrophages are present in all tissues and body compartments under homeostatic physiological conditions. Importantly, they play a key role in pathological inflammatory processes when disturbed. They can quickly produce large amounts of inflammatory cytokines in response to danger signals. Macrophages can recognize muramyl dipeptide (MDP) through nucleotide-binding oligomerization domain (NOD)-like receptors, subsequently activating the NF-κB signaling pathway and producing proinflammatory cytokines. Erbin can bind to NOD2 and inhibit MDP-induced NF-κB activation, thus participating in the regulation of inflammatory response. Stabilizing or enhancing Erbin expression is essential for suppressing inflammatory responses. In this study, we used a deubiquitination enzyme plasmid library to screen for a key deubiquitinase, VCPIP1, which interacts with Erbin and influences its stability through deubiquitination modification. We investigated whether VCPIP1 affects inflammation using MDP-stimulated RAW 264.7 and BMDMs cells. The results showed that VCPIP1 deficiency reduced Erbin expression and increased NF-κB phosphorylation. Additionally, VCPIP1 deficiency promoted the release of inflammatory factors (IL-1β, IL-6, and TNF-α) in RAW 264.7 cells and BMDMs. This study further expands the role of deubiquitinases (DUBs) in inflammation, providing new insights for the prevention and treatment of sepsis, tumors, immune diseases, and other inflammatory reactions.

Comparison of inflammatory mediator cytokine responses to inactivated virus platform COVID-19 vaccines between elderly and young adult populations

The coronavirus disease 2019 (COVID-19) pandemic has encouraged global vaccine research, yet vaccine effectiveness in the elderly remains a concern due to immunosenescence. The aim of this study was to compare the cytokine response elicited by an inactivated virus-based COVID-19 vaccine between elderly and young adults, focusing on key cytokines involved in cellular and humoral immunity: tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2, IL-6, IL-10, and interferon-gamma (IFN-γ). A cross-sectional study was conducted in the Jakarta-Bogor region of Indonesia from January 2023 to December 2023. The study population was divided into two age cohorts: elderly (60−85 years) and younger adults (30−40 years). Blood samples were collected twice, after the first booster dose and four weeks after the second booster dose. Serum cytokine concentrations were measured using Luminex assays with microparticles conjugated to monoclonal antibodies against TNF-α, IL-2, IL-6, IL-10, and IFN-γ. Comparisons of the cytokine levels were conducted using Student’s t-tests or Mann-Whitney U tests as appropriate. A total of 74 individuals were included, with 37 each in the elderly and young adult groups. The results showed significant differences in cytokine responses between the two age groups. After the first booster, the levels of IL-6 and IFN-γ were significantly higher in young adults compared to the elderly. After the second booster, the levels of IL-6 were still significantly higher in the young adult group compared to the elderly group (p=0.001). Data indicated that after the second booster dose, the levels of TNF-α increased significantly in the young adult group only (p=0.004), while the levels of IL-2 (p=0.040) and IFN-γ (p=0.006) increased in the elderly group only compared to after the first dose. IL-10 levels increased in both groups (both had p=0.020). This study highlights that young adults had stronger pro-inflammatory responses, while the elderly relied more on IL-2 and IFN-γ for T-cell immunity, suggesting the need for vaccination strategies for the elderly to optimize immune responses.

Amyloid beta-induced signalling in leptomeningeal cells and its impact on astrocyte response.

The pathological signature of Alzheimer's disease (AD) includes the accumulation of toxic protein aggregates, mainly consisting of amyloid beta (Aβ). Recent strides in fundamental research underscore the pivotal role of waste clearance mechanisms in the brain suggesting it may be an early indication of early onset AD. This study delves into the involvement of leptomeningeal cells (LMCs), crucial components forming integral barriers within the clearance system, in the context of AD. We examined the inflammatory cytokine responses of LMCs in the presence of Aβ, alongside assessments of LMC growth response, viability, oxidative stress, and changes in vimentin expression. The LMCs showed no changes in growth, viability, oxidative stress, or vimentin expression in the presence of Aβ, indicating that LMCs are less susceptible to Aβ damage compared to other CNS cells. However, LMCs exhibited a unique pro-inflammatory response to Aβ when compared to an LPS inflammatory control, showing an mRNA expression of pro-inflammatory cytokines such IL-6, IL-10 and IL-33 but no changes in IL-1α and IL-1β. Furthermore, LMCs influenced the astrocyte response to Aβ, as conditioned media from Aβ-treated LMCs was observed to downregulate somatic S100β in astrocytes. We also investigated whether the JAK/STAT3 pathway was involved in the Aβ response of the LMCs, as this pathway has been shown to be activated in astrocytes and neurons in the presence of Aβ. JAK/STAT3 activation was assessed through phosphorylated STAT3, revealing that JAK/STAT3 was not active in the cells when in the presence of Aβ. However, when JAK1 and JAK2 were inhibited, cytokine protein levels of IL7, IL10, IL15 and IL33 levels, which had shown alteration when LMCs were treated with Aβ, returned to base levels. This indicates that although JAK1/STAT3 and JAK2/STAT3 are not the direct pathway for Aβ response in LMCs, JAK1 and JAK2 may still play a role in regulating cytokine levels, potentially through indirect means or crosstalk. Overall, our findings reveal that LMCs are resilient to Aβ toxicity and suggest that JAK1/STAT3 and JAK2/STAT3 does not play a central role in the inflammatory response, providing new insights into the cellular mechanisms underlying AD.

Amelioration of Systemic Amyloidosis by Blocking IL-17A and Not by IL-17F, and Arteriosclerosis by Blocking Both IL-17A and IL-17F in an Inflammatory Skin Mouse Model.

There are comorbidities and complications in atopic dermatitis and psoriasis that often occur after the appearance of skin inflammation. Statistically, data show that patients with psoriasis and atopic dermatitis have a shorter life expectancy than patients without psoriatic dermatitis, due to the occurrence of arteriosclerosis, myocardial infarction, and cerebral infarction. Many types of skin inflammation are treated with various antibody preparations, and marked improvement in patients' quality of life can be achieved. The next theme is to understand the pathogenesis of arteriosclerosis, myocardial infarction, stroke, and other complications associated with dermatitis and to find treatments and drugs to reduce their occurrence. The skin, a crucial immune organ, generates large amounts of inflammatory cytokines in response to various stimuli, leading to systemic inflammation and potential damage to internal organs. The link between inflammatory skin conditions like psoriasis and atopic dermatitis with serious health complications such as vascular disorders and systemic amyloidosis has been increasingly recognized. In psoriasis, biological treatments targeting Interleukin (IL)-17A, a key cytokine, have shown promise in reducing cardiovascular risks. Recent developments include treatments that target both IL-17A and IL-17F in the psoriasis field, though each cytokine's impact on internal organ damage is still under debate. Among visceral complications secondary to dermatitis, systemic amyloidosis and atherosclerosis have been reported to be controlled by suppressing IL-17 in the early stages of dermatitis. Still, it remains unclear whether suppressing IL-17 prevents organ damage in the late stages of persistent severe dermatitis. A study using a long-lasting dermatitis mouse model that overexpressed human caspase-1 in keratinocytes (Kcasp1Tg) investigated the effects of deleting IL-17A and IL-17F on visceral complications. Cross-mating Kcasp1Tg with IL-17A-, IL-17F-, and IL-17AF-deficient mice assessed the skin and visceral organs histologically, and RT-PCR analysis of aortic sclerosis markers was performed. Despite less improvement in dermatitis, deletion of IL-17A in Kcasp1Tg mice showed promising results in reducing multiple organ amyloidosis. On the other hand, the effect was observed in both IL-17A and IL-17F deleted mice for aortic sclerosis. The inhibition of IL-17A and IL-17F was suggested to reduce the risk of developing comorbidities in internal organs. IL-17A and IL-17F were found to act similarly or produce very different results, depending on the organ.

Omega-3 Fatty Acids and Neuroinflammation in Depression: Targeting Damage-Associated Molecular Patterns and Neural Biomarkers.

Major Depressive Disorder (MDD) is a prevalent mental health condition with a complex pathophysiology involving neuroinflammation, neurodegeneration, and disruptions in neuronal and glial cell function. Microglia, the innate immune cells of the central nervous system, release inflammatory cytokines in response to pathological changes associated with MDD. Damage-associated molecular patterns (DAMPs) act as alarms, triggering microglial activation and subsequent inflammatory cytokine release. This review examines the cellular mechanisms underlying MDD pathophysiology, focusing on the lipid-mediated modulation of neuroinflammation. We explore the intricate roles of microglia and astrocytes in propagating inflammatory cascades and discuss how these processes affect neuronal integrity at the cellular level. Central to our analysis are three key molecules: High Mobility Group Box 1 (HMGB1) and S100 Calcium Binding Protein β (S100β) as alarmins, and Neuron-Specific Enolase (NSE) as an indicator of neuronal stress. We present evidence from in vitro and ex vivo studies demonstrating how these molecules reflect and contribute to the neuroinflammatory milieu characteristic of MDD. The review then explores the potential of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) as neuroinflammation modulators, examining their effects on microglial activation, cytokine production, and neuronal resilience in cellular models of depression. We critically analyze experimental data on how ω-3 PUFA supplementation influences the expression and release of HMGB1, S100β, and NSE in neuronal and glial cultures. By integrating findings from lipidomic and cellular neurobiology, this review aims to elucidate the mechanisms by which ω-3 PUFAs may exert their antidepressant effects through modulation of neuroinflammatory markers. These insights contribute to our understanding of lipid-mediated neuroprotection in MDD and may inform the development of targeted, lipid-based therapies for both depression and neurodegenerative disorders.

Inflammatory cytokine responses in pediatric tuberculosis with or without SARS-CoV-2 seropositivity

To characterize the inflammatory cytokine profiles in children with TB in the presence and absence of SARS-CoV2 seropositivity. This study evaluated cytokine responses in two groups of children with TB: CoV2+ (TB and SARS-CoV2 seropositive) and CoV2- (TB and SARS-CoV2 seronegative). Each group had 30 children, and cytokine levels were measured at baseline, months 3and 6. At baseline, CoV2+ children exhibited significantly elevated levels of cytokines, including IFN-γ, IL-2, TNFα, IL-1α, and IL-6, and reduced levels of IL-1β and IL-18, compared to CoV2- children. No significant differences in cytokine levels between the groups were observed at months 3 and 6. Additionally, a general decline in cytokine levels was noted over the course of treatment in both groups. A positive correlation was found between most cytokines and SARS-CoV2 IgG spike protein levels at baseline and at month 3 in the CoV2+ group. This study is one of the first studies to characterize the systemic inflammatory responses in SARS-CoV2 seropositive and seronegative children with TB from a TB endemic country. The findings enhance our understanding of the immunopathogenesis of TB and SARS-CoV2 seropositivity in children and may inform future therapeutic strategies.

Subduing the Inflammatory Cytokine Storm

The inflammatory cytokine response is essential for protective immunity, yet bacterial and viral pathogens often elicit an exaggerated response (“cytokine storm”) harmful to the host that can cause multi-organ damage and lethality. Much has been published recently on the cytokine storm within the context of the coronavirus pandemic, yet bacterial sepsis, severe wound infections and toxic shock provide other prominent examples. The problem of the cytokine storm is compounded by the increasing incidence of multidrug-resistant bacterial strains. We created an incisive molecular tool for analyzing the role of the B7/CD28 costimulatory axis in the human inflammatory response. To attenuate the cytokine storm underlying infection pathology, yet preserve host defenses, we uniquely targeted the engagement of CD28 with its B7 co-ligands by means of short peptide mimetics of the human CD28 and B7 receptor homodimer interfaces. These peptides are not only effective tools for dissecting mechanism but also serve to attenuate the inflammatory response as a broad host-oriented therapeutic strategy against the cytokine storm. Indeed, such peptides protect mice from lethal Gram-positive bacterial superantigen-induced toxic shock even when dosed in molar amounts well below that of the superantigen and show promise in protecting humans from the severe inflammatory disease necrotizing soft tissue infections (‘flesh-eating’ bacterial sepsis) following traumatic wound injuries.

Exploring and validating the necroptotic gene regulation and related lncRNA mechanisms in colon adenocarcinoma based on multi-dimensional data.

Necroptosis is intimately associated with the initiation and progression of colon adenocarcinoma (COAD). However, studies on necroptosis-related genes (NRGs) and the regulating long non-coding RNAs (NRGlncRNAs) in the context of COAD are limited. We retrieved the cancer genome atlas (TCGA) to collect datasets of NRGs and NRGlncRNAs on COAD patients. The risk model constructed using Cox and least absolute shrinkage and selection operator (LASSO) regression was then employed to identify NRGs and NRGlncRNAs with prognostic significance. Subsequently, we validated the results using gene expression omnibus (GEO) datasets from different populations, conducted Mendelian randomization (MR) analysis to explore the potential causal relationships between prognostic NRGs and COAD, and conducted cell experiments to verify the expression of prognostic NRGlncRNAs in COAD. Furthermore, we explored potential pathways and regulatory mechanisms of these prognostic NRGlncRNAs and NRGs in COAD through enrichment analysis, immune cell correlation analysis, tumor microenvironment analysis, immune checkpoint analysis, tumor sample clustering, and so on. We identified eight NRGlncRNAs (AC245100.5, AP001619.1, LINC01614, AC010463.3, AL162595.1, ITGB1-DT, LINC01857, and LINC00513) used for constructing the prognostic model and nine prognostic NRGs (AXL, BACH2, CFLAR, CYLD, IPMK, MAP3K7, ATRX, BRAF, and OTULIN) with regulatory relationships with them, and their validation was performed using GEO and GWAS datasets, as well as cell experiments, which showed largely consistent results. These prognostic NRGlncRNAs and NRGs modulate various biological functions, including immune inflammatory response, oxidative stress, immune escape, telomere regulation, and cytokine response, influencing the development of COAD. Additionally, stratified analysis of the high-risk and low-risk groups based on the prognostic model revealed elevated expression of immune cells, increased expression of tumor microenvironment cells, and upregulation of immune checkpoint gene expression in the high-risk group. Finally, through cluster analysis, we identified tumor subtypes, and the results of cluster analysis were essentially consistent with the analysis between risk groups. The prognostic NGRlncRNAs and NRGs identified in our study serve as prognostic indicators and potential therapeutic targets for COAD, providing a theoretical basis for the clinical diagnosis and treatment of COAD and offering guidance for further research.