Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally. The prevalence of NAFLD in the general population is estimated to be 25-30 %, making it the most common chronic liver condition in China as well as worldwide. Given the escalating disease burden and the scarcity of effective therapeutic interventions, there is a pressing unmet clinical need. Consequently, the development of novel pharmaceuticals has emerged as a pivotal research focus in recent years. Moreover, the advent of nano-delivery technology offers innovative solutions for NAFLD drug therapy. This paper presents a comprehensive examination of the pathogenesis and therapeutic targets of NAFLD. It critically reviews the latest advancements in nanomedicine research pertinent to NAFLD treatment. The review synthesizes a broad range of research findings to bridge the gap between current knowledge and emerging therapeutic strategies, and aims to inform and guide future research directions in NAFLD management.

Yinchen (YC), the dried aerial parts of the medicinal plant Artemisia capillaris Thunb. (family Asteraceae), is primarily distributed across the Asia-Pacific Region. Although YC exhibits clinically validated efficacy against immune hemolytic disorders, its mechanistic underpinnings remain insufficiently elucidated in pharmacological research. This study investigates the potential targets and mechanisms of YC in treating immune hemolysis based on network pharmacology and bioinformatic analysis. Additionally, it aims to verify quercetin's anti-complement activity and inhibition of IL-6-induced STAT3 activation, a key component of YC, through in vitro experiments, molecular docking and molecular dynamics simulations. 13 active components in YC with 143 putative targets were identified by Network pharmacology. Quercetin, beta-sitosterol, and isorhamnetin were top-ranked by target count. 1231 gene targets related to immune hemolysis, with 60 overlapping targets mapping to both YC and the disease were identified. Quercetin exhibited inhibitory activity against both classical and alternative complement pathways, with IC50 values of 528.3 mg/L and 212.5 mg/L, respectively. Quercetin (80 μM) suppressed IL-6-induced IgG secretion and attenuated STAT3 signaling in murine splenic lymphocytes, as evidenced by decreased levels of STAT3 mRNA expression, STAT3 and phosphorylated STAT3 (p-STAT3) proteins. Molecular docking analysis revealed quercetin's putative binding affinity to key complement system components (C1, C2, C3, C4, C5, C8, C9, Factor B) and IL-6, suggesting a dual mechanism of complement pathway modulation and IL-6/IL-6R interaction blockade. Simulation studies confirmed the stable interaction between C1s, C3, C5 and IL-6 and quercetin. Quercetin, a key component of Yinchen used in treating immune hemolysis, demonstrates anti-complement activity and can inhibit IL-6-induced STAT3 activation in vitro.

Severe dengue is characterized by vascular leakage triggered by a hyperinflammatory response, though the underlying mechanisms remain unclear. Our previous mouse model study highlighted the importance of small intestine in severe disease and identified key cytokines (IL-17A, TNF-α, and IL-6) involved. Here, we used a Fixed RNA Profiling assay to characterize key cytokine- and effector-producing cells, along with their receptor expression. Type 3 innate lymphoid cells (ILC3), Th17 cells, and γδ T cells emerged as pathologically relevant IL-17A/F-producing cells. These cells expressed IL-1β and IL-23 receptors, underscoring the significance of these signaling pathways. IL-1β was produced by M2-like macrophages, dendritic cells, and neutrophils, whereas M1-like macrophages, which differentiated post-infection, produced IL-23, TNF-α, and IL-6, acting as initiators and amplifiers of the cytokine storm. Newly differentiated neutrophils produced IL-1β and effector molecule matrix metalloprotease-8, suggesting a dual role in exacerbating the cytokine storm and directly mediating vascular leakage. Identified macrophages and neutrophils exhibited atypical characteristics. These findings provide new pathological insights into severe dengue and broader mechanism underlying cytokine storm-related diseases.

Autoimmune diseases (AIDs) are a group of disorders in which the immune system mistakenly attacks the body's own tissues, characterized by the loss of tolerance to self-antigens and destruction of tissues. Aging is a natural process of physiological decline that also alters the immune system, a condition known as immunosenescence. During immunosenescence, the immune system undergoes various changes, including modifications and antigenicity of self-antigens, abnormalities in the quantity, phenotype, and function of lymphocytes and antibodies, as well as a narrowing of the B and T cell receptor repertoire, changes that may increase susceptibility to AIDs. Additionally, senescent immune cells and the senescence-associated secretory phenotype (SASP) contribute to target organ involvement in AIDs, exacerbating chronic inflammation and tissue damage. Mitochondrial dysfunction and metabolic imbalances in AIDs lead to the accumulation of senescent cells, which act as upstream drivers of immunosenescence. In this review, we summarize the bidirectional relationship between AIDs and immunosenescence, as well as its potential mechanisms. Therapeutic approaches targeting immunosenescence in AIDs remain at an early stage. Strategies aimed at resetting or reversing the aging immune system are expected to become a novel direction in the future.

Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.

The lung-brain axis represents a complex bidirectional communication network that is pivotal in the crosstalk between respiratory and neurological functions. This review summarizes the current understanding of the mechanisms and protein markers that mediate the effects of lung diseases on brain health.

In this review, we explore the mechanisms linking lung injury to neurocognitive impairments, focusing on neural pathways, immune regulation and inflammatory responses, microorganism pathways, and hypoxemia. Specifically, we highlight the role of the vagus nerve in modulating the central nervous system response to pulmonary stimuli; Additionally, the regulatory function of the immune system is underscored, with evidence suggesting that lung-derived immune mediators can traverse the blood-brain barrier, induce neuroinflammation and cognitive decline; Furthermore, we discuss the potential of lung microbiota to influence brain diseases through microbial translocation and immune activation; Finally, the impact of hypoxemia is examined, with findings indicating that it can exacerbate cerebral injury via oxidative stress and impaired perfusion. Moreover, we analyze how pulmonary conditions, such as pneumonia, ALI/ARDS, and asthma, contribute to neurological dysfunction. Prolonged mechanical ventilation can also contribute to cognitive impairment. Conversely, brain diseases (e.g., stroke, traumatic brain injury) can lead to acute respiratory complications. In addition, protein markers such as TLR4, ACE2, A-SAA, HMGB1, and TREM2 are crucial to the lung-brain axis and correlate with disease severity. We also discuss emerging therapeutic strategies targeting this axis, including immunomodulation and microbiome engineering. Overall, understanding the lung-brain interplay is crucial for developing integrated treatment strategies and improving patient outcomes. Further research is needed to elucidate the molecular mechanisms and foster interdisciplinary collaboration.

Long-COVID immunopathogenesis involves diverse factors. We longitudinally characterize hospitalized COVID-19 patients, examining the role of SARS-CoV-2 RNAemia and inflammation in immune dysregulation.

Hospitalized patients are evaluated during acute infection (T0), 3 months post-symptom onset (T1), and 3 years if symptoms persisted (T2). Immune profile includes characterization of SARS-CoV-2-specific/non-specific T/B cells (flow cytometry) and antibodies (ELISA, neutralization, ADCC). RNAemia and cytokines are quantified (RT-PCR, cytometric beads array) and correlated.

non-parametric cross-sectional, longitudinal and correlation analyses.

Here we show 48 hospitalized individuals during acute COVID-19, 38 exhibit early persistent symptoms (EPS+) 3 months post-symptoms onset, 10 do not (EPS-). Groups are comparable for age, sex, co-morbidities. The EPS+ shows fatigue, dyspnoea, anosmia/dysgeusia, diarrhea, chronic pain, mnestic disorders. Over time, they show a reduction of neutralization ability and total SARS-CoV-2-specific CD4 T cells, with increased total CD4 TEMRA, and failure to increase RBD-specific B cells and IgA+ MBCs. EPS+ patients show higher levels of T0-IFN-γ + CD4 TEMRA, T1-IL-2 + CD4 TEM and T1-TNF-α + CD4 cTfh. In EPS+, baseline SARS-CoV-2 RNAemia positively correlates with CD4 TEMRA, follow-up SARS-CoV-2 RNAemia with ADCC. Among 38 EPS+ individuals at T1, 33 are evaluated 3 years after infection, 5 are lost at follow-up. 10/33 EPS+ show long-term symptoms (late persistent symptoms, EPS + LPS+), whereas 23/33 fully recover (EPS + LPS-). Antibodies, RNAemia, and cytokines show no differences between/within groups at any time point.

Early persistent symptoms are associated with multi-layered SARS-CoV-2-specific/non-SARS-CoV-2-specific immune dysregulation. The shift towards non-Ag-specific TEMRA and ADCC trigger in EPS+ may relate to SARS-CoV-2 RNAemia. Early immune dysregulation does not associate with long-term persistent symptoms. Further research on SARS-CoV-2 RNAemia and early immune dysregulation is needed.

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.

Psychological stress is the most common psychological comorbidity and a significant triggering factor of vitiligo. Moderate to severe psychological stress can markedly affect the efficacy of vitiligo treatment. However, the specific mechanisms underlying its involvement remain insufficiently studied.

Chronic unpredictable mild stress (CUMS)-induced major depressive disorder (MDD)-like behavior was modeled in C57BL/6 mice alongside wild-type mice to investigate differences in vitiligo pathogenesis. White spot tissues from mouse tails were subjected to high-throughput transcriptomic sequencing (RNA-seq). In vitro experiments utilized β-galactosidase, P16, and P21 to assess IFN-γ-induced senescence. The effects of exogenous IL-6 on fibroblast senescence were assessed, and the role of blocking the IL-6 autocrine loop with an IL-6R inhibitor in reversing IFN-γ-induced fibroblast senescence was evaluated.

CUMS-induced MDD -like mice exhibited significantly lower body mass index and sugar-water preference index compared to wild-type mice, and their vitiligo severity was markedly increased. Transcriptomic sequencing revealed significant upregulation of cellular senescence and JAK-STAT signaling pathways in white spot tissues of depressive-like vitiligo mice. In vitro findings indicated that IFN-γ induced fibroblast senescence via activation of the JAK2-STAT3 signaling pathway, which subsequently promoted melanocyte apoptosis and increased IL-6 secretion and IL-6R expression. Exogenous IL-6 further activated the JAK2-STAT3 signaling pathway, induced fibroblast senescence, and synergistically intensified IFN-γ-induced fibroblast senescence.

Excessive activation of the IL-6 autocrine loop, synergizing with IFN-γ to aggravate fibroblast senescence and promote melanocyte apoptosis. Blocking the IL-6 autocrine loop may serve as an effective approach to mitigate the impact of CUMS on vitiligo pathogenesis and treatment efficacy.

T helper 17 and Regulatory T cells (Th17 and Treg, respectively) are two well-described lymphocyte subsets with opposing actions. The divergent fates of Th17 and Treg cells are accounted for, at least in part, by molecular antagonism that occurs between their respective specific transcription factors, RORγt and Foxp3. An imbalance between Th17 and Treg cells may lead to tissue inflammation and is associated with certain types of autoimmunity. In order to understand the heterogeneity and dynamics of the differentiation process, we studied Th17/Treg cell differentiation of naïve cells in vitro, using RORγtGFPFoxp3RFP dual-reporter mouse. Flow cytometry revealed the consistent emergence of a population of double positive RORγt+Foxp3+ (DP) cells during the early stages of Th17 cell differentiation. These DP cells are closely related to RORγt+ single positive (SPR) cells in terms of global gene expression. Nevertheless, for some genes, DP cells share an expression pattern with Foxp3+ single positive (SPF) Treg cells, most importantly by reducing IL17 levels. Using time-lapse microscopy, we could delineate the expression dynamics of RORγt and Foxp3 at a clonal level. While the RORγt expression level elevates early during differentiation, Foxp3 rises later and is more stable upon environmental changes. These distinct expression profiles are independent of each other. During differentiation and proliferation, individual cells transit between SPR, DP, and SPF states. Nevertheless, the differentiation of sister cells within a clone progeny was highly correlated. We further demonstrated that sorted SPR and DP populations were not significantly affected by changes in their environment, suggesting that the correlated fate decision emerged at early time points before the first division. Overall, this study provides the first quantitative analysis of differentiation dynamics during the generation of DP RORγt+Foxp3+ cells. Characterizing these dynamics and the differentiation trajectory could provide a profound understanding and be used to better define the distinct fates of T cells, critical mediators of the immune response.

Autoimmune encephalitides (AEs) are neurological disorders caused by autoantibodies against neuronal and glial surface proteins. Nearly 20 years after their discovery, AE have evolved from being frequently misdiagnosed and untreated to a growing group of increasingly well-characterized conditions where patients benefit from targeted therapeutic strategies. This narrative review provides an immunological perspective on AE, focusing on NMDAR, CASPR2 and LGI1 encephalitis as the three most common forms of AE associated with anti-neuronal surface autoantibodies. We examine the autoreactive B cell subsets, the tolerance checkpoints that may fail, and the known triggers and predispositions contributing to disease. In addition, we discuss the roles of other immune cells, including T cells and microglia, in the pathogenesis of AE. By analyzing therapeutic strategies and treatment responses we draw insights into AE pathophysiology. Written at a time of transformative therapeutic advancements through cell therapies this work underscores the synergy between detailed immunological research and the development of innovative therapies.

Inflammatory bowel disease (IBD) refers to a group of chronic inflammatory disorders impacting the gastrointestinal (GI) tract. It represents a significant public health challenge due to its rising global incidence and substantial impact on patients' quality of life. Emerging research suggests a pivotal role of the human microbiome in IBD pathogenesis. Bacteriophages, integral components of the human microbiome, are indicated to influence the disease onset, progression, and therapeutic strategies. Here, we review the effect of bacteriophages on the pathogenesis of IBD and, more specifically, on the gut bacteria, the systemic immunity, and the susceptibility genes. Additionally, we explore the potential therapeutic use of the bacteriophages to modify gut microbiota and improve the health outcomes of IBD patients. This review highlights the potential of therapeutic bacteriophages in regulating gut microbiota and modulating the immune response to improve health outcomes in IBD patients. Future studies on personalized bacteriophage therapy and its integration into clinical practice could advance treatment strategies for IBD.

Endometriosis, an inflammatory disease, is characterized by the aberrant presence of endometrial tissues at ectopic locations. Accumulating evidence suggests that inflammatory cells, such as interleukin-17 (IL-17)-producing cells, may be involved in the pathogenesis of endometriosis. This investigation assessed the frequency of IL-17A (commonly known as IL-17)-producing cells in peripheral blood mononuclear cells (PBMCs), ectopic, and eutopic endometrial tissues in patients with endometriosis compared to non-endometriotic subjects. PBMCs, ectopic, and eutopic endometrial tissues were collected from 23 patients with endometriosis. PBMCs and endometrial tissues from 20 non-endometriotic women were used as the control group. The frequency of T helper 17 (TH17) lymphocytes in PBMCs was assessed using flow cytometry, and the expression level of IL-17 in eutopic and ectopic endometrial tissues was evaluated through immunohistochemistry. The percentage of TH17 and IL-17-producing lymphocytes was significantly higher in the PBMCs of patients with endometriosis compared to non-endometriotic subjects (P < 0.01 and P < 0.001, respectively). The expression of IL-17 protein in ectopic (P < 0.001) and eutopic (P < 0.05) endometrial tissues of patients with endometriosis increased compared to controls' endometrial tissue. Furthermore, the eutopic endometrium of patients with endometriosis showed a higher expression of IL-17 protein than the eutopic endometrial tissue of control subjects (P < 0.05). The findings suggest that the higher frequency of IL-17-producing cells in the PBMCs and endometrial tissues of patients with endometriosis contributes to the pathogenesis of endometriosis.

Ulcerative colitis (UC)-induced colitis-associated colorectal cancer (CAC) has a worse prognosis than sporadic colorectal cancer. And with the incidence of ulcerative colitis on the rise, it is critical to identify new therapeutic targets in time to stop the progression of inflammation to cancer. Through immunohistochemistry (IHC) and Gene Expression Omnibus (GEO) database analysis, we acquired the gene M2DEG, which is differentially expressed in M2 macrophages. The impact of M2DEG on the immune environment and clinical variables was confirmed through various data sets and actual tissue samples. Our findings indicate that patients with UC exhibiting reduced M2 macrophage infiltration tend to have more widespread disease, elevated endoscopic Mayo scores, and a higher probability of developing CAC. Through examining the string of M2DEG between UC and CAC, THBS2 emerged as a key marker. Elevated levels of THBS2 were notably linked to reduced overall survival (OS) and progression-free survival (RFS), and this heightened THBS2 expression played a crucial role in the spread of tumors, as verified by immunohistochemical studies. To sum up, patients with UC exhibiting reduced M2 macrophage infiltration have a higher propensity for CAC development, making THBS2 a crucial focus for converting UC into CAC. Furthermore, identifying antibody analogues targeting THBS2 could potentially lower the likelihood of CAC transformation in patients with UC.

Autoimmune hepatitis (AIH) is an immunoinflammatory chronic liver disease with increasing prevalence worldwidely, lacking of effective medicine. Herpetospermum caudigerum Wall. (HC) is a traditional Tibetan medicine used to treat liver diseases for thousands of years. However, investigation into the effects of HC in AIH remains scarce.

Our study aimed to explore the effects and mechanisms of ethyl acetate extract from the seeds of HC (HCDEAE) against concanavalin A (Con A)-induced liver impairment in mouse.

HCDEAE was extracted from the seeds of HC, then characterized by UPLC-Q-TOF/MS. Con A-induced AIH mice were used to investigate the impacts of HCDEAE on liver impairment, T cells differentiation, gut microbiota and its derived metabolites, intestinal barrier impairment and inflammation, as well as the mechanisms of HCDEAE in liver in AIH.

HCDEAE (90 mg/kg, i.g.) effectively alleviated Con A-induced hepatic pathological damage, suppressed elevation of serum ALT, AST, IFN-γ, and TNF-α; in spleen, HCDEAE attenuated spleen impairment, elevated the percentage of CD4+CD25+ cells and FOXP3 gene expression, inhibited up-regulation of RORγt gene expression and IL-17; in liver, HCDEAE down-regulated IL-17, elevated FOXP3 gene expression and IL-10, increased the protein and gene expression of TGF-β1; in colon, HCDEAE attenuated intestinal barrier impairment, inhibited down-regulation of Occludin and ZO-1, and relieved elevation of IL-1β, as well as re-profiled the gut microenvironment. Furthermore, HCDEAE demonstrated the ability to elevate tryptophan metabolism among kynurenine pathway, activate IDO1/KYN pathway and inhibit PI3K/AKT/NF-κB signaling pathway in liver of AIH mice.

Pretreatment with HCDEAE (90 mg/kg·d-1, i.g.) for 9 days could effectively alleviate the liver inflammation and injure, protect intestinal barriers, attenuate spleen impairment, maintain Treg-Th17 cell equilibrium in Con A-induced AIH mice, via re-profiling gut microbiota, modulation of tryptophan metabolism in the gastrointestinal tract and in liver, to activate IDO1/KYN pathway and inhibit the abnormal activation of PI3K/AKT/NF-κB signaling pathway in liver. The present study highlighted the potential of HCDEAE as a drug candidate for AIH.

Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.

The TYK2:p.Pro1104Ala (rs34536443) hypomorph variant has been associated with protection against numerous autoimmune disorders. Thus, its mechanism of action becomes of great interest. Here, consistent with the participation of activated immune cells in autoimmunity, we show that the variant regulates the levels of immune cells at a human, general population level and is associated particularly with higher levels of T and B lymphocytes, especially the naïve (non-activated) compartment. Also, consistent with a protective function in autoimmunity, the level of regulatory CD4+ T cells was increased. Thus, this variant decreases immune activation thereby protecting from autoimmunity. Our work links the cellular mechanism regulated by the TYK2:p.Pro1104Ala variant to autoimmunity protection and supports TYK2 as a therapeutic target in autoimmunity.

The insufficiency of current Porcine Epidemic Diarrhea (PED) vaccines against highly pathogenic strains highlights the critical importance of enhancing mucosal immunity in the prevention and control of porcine enteric viral diseases. Due to limited research platforms, the understanding of the porcine mucosal immune system and its response mechanisms remains incomplete. This study employed prokaryotic expression and purification methods to obtain eight essential cytokines involved in mucosal immune responses (CD40L, IL-2, IL-6, TNF-α, IL-13, IL-17α, TGF-β, APRIL). By utilizing various cell models including porcine intestinal organoids, IPEC-J2, Vero-E6, porcine peripheral blood lymphocytes, and porcine Peyer's patch lymphocytes, the functions of these eight cytokines were identified through flow cytometry, immunoblotting, relative quantitative PCR, and CFSE proliferation assays. The results demonstrate that all eight purified proteins exhibit both protein activity and function. The purification of these molecules lays the groundwork for further exploration of the mucosal barrier of pigs and mucosal immune-related studies, as well as providing research tools for the prevention and control of enteric viral diseases in pigs.

The formation of tongue coating is closely related with the differentiation of the lingual dorsal mucosa, and a great deal of evidence shows that the variation of tongue coating reflects the pathological and physiological state of the gastric mucosa. However, the detailed mechanism remains elusive. This study established a rat model of gastric intestinal metaplasia (GIM) with 2% sodium salicylate and 20 mmol/L of deoxycholate sodium, and used single-cell RNA sequencing (scRNA-seq) to reveal the cell landscape of tongue dorsal mucosa. In comparison to the control group, the tongue dorsal mucosa of GIM rats became grayish-white, and the histologic characteristics presented an uneven distribution of tongue papilla with many immune cells in the submucosal layer. The expressive levels of pro-inflammatory factors (IL-1β, IL-6, and IL-17) were significantly higher in GIM rats than in the control group. Stratified analysis revealed the significant downregulation of autophagy marker gene Map1lc3a in neutrophils and T cells, and the significant downregulation of cuproptosis marker gene Dlst in fibroblasts of the tongue dorsal mucosa in GIM rats. These changes were closely related to mucosal inflammation and impaired tissue barrier integrity. Significantly, the expression of several keratin genes (Krt7, Krt8, Krt13, Krt16, and Krt76) was significantly downregulated, as well as the expression of the bitter taste receptor gene Rtp4 and the sweet taste receptor gene Tas1r2 in the GIM rats. The data indicated that fewer cells entered regulated cell death in immune cells of tongue mucosa, a more active inflammatory response occurred, the keratinization of tongue dorsal mucosal cells was inhibited, and the taste perception function was weakened. The results bring new perspectives on tongue coating in the application of gastric disorders. Characteristics of the tongue dorsum mucosal cell landscape in the rats with gastric intestinal metaplasia. The abundances of T cells, neutrophils, and macrophages were upregulated, and the autophagy marker gene Map1lc3a in T cells and neutrophils was downregulated, which indicated an actively inflammatory immune response. Downregulation of cuprotosis marker gene Dlst in fibroblasts suggested potential damage to the mucosal barrier. Meanwhile, the expression of bitter receptor Rtp4 and sweet receptor Tas1r2 in mesenchymal stem cells was downregulated. The cell communication ability was reduced, especially between mesenchymal stem cells and epithelial cells. In a word, the abnormal status of tongue dorsum mucosa may accompany the development of gastric intestinal metaplasia.

The treatment of chronic viral infections can often bring viral replication under control. However, chronic immune activation persists and can lead to the development of comorbid conditions, such as cardiovascular disease and cancer. This is particularly true for people living with HIV (PLWH), who have significantly more extracellular vesicles from membrane budding, also called plasma microparticles (MPs), than healthy individuals (HDs), and a much more immunomodulatory phenotype. We hypothesized that the number and phenotypic heterogeneity of MPs can trigger a functional remodeling of immune responses in PLWH, preventing full immune restoration.

We investigated the rapid impact of three types of MPs - derived from membrane budding in platelets (CD41a+ PMPs), monocytes (CD14+ MMPs) and lymphocytes (CD3+ LMPs) in the plasma of PLWH or HDs-on four cell types (CD4+ and CD8+T lymphocytes, monocytes and DCs).

These investigations of the short multiple interactions and functions of MPs with these cells revealed an increase in the secretion of cytokines such as IFNg, IL2, IL6, IL12, IL17 and TNFa by the immune cells studied following interactions with MPs. We show that this functional remodeling of immune cells depends not only on the number, but also on the phenotype of MPs.

These data suggest that the large numbers of MPs and their impact on functional remodeling in PLWH may be incompatible with the effective control of chronic infections, potentially leading to chronic immune activation and the onset of comorbid diseases.

Neutrophils are scarce in healthy skin but infiltrate lesions of hidradenitis suppurativa (HS) patients. Activated neutrophils release proinflammatory neutrophil extracellular traps (NETs), which have been implicated in the pathophysiology of HS. This study aimed to describe the distribution of NETs relative to the features of HS skin lesions and reveal whether serum NET markers were elevated in association with disease activity.

Immunohistochemistry assessed the distribution of the key NET component citrullinated histone H3 (CitH3) in lesional, perilesional, and unaffected HS skin. Several markers of NETs (nucleosomes, calprotectin, and CitH3) were quantified in HS serum with ELISA.

HS lesional skin biopsies showed increased CitH3-positive staining compared to unaffected skin. This signal was widely distributed across both lesional and perilesional regions of HS skin and was associated with HS structures such as the lining of epithelialized skin tunnels. Moreover, several NET-associated markers were elevated in the serum of HS patients compared to healthy volunteers and correlated with each other. Finally, serum NET markers showed significant elevation in patients with moderate to severe disease activity based on IHS-4 scores, compared to those with no or mild activity.

Elevated NET markers are widely distributed in HS skin and serum. These data indicate that NET-associated markers in serum are candidate biomarkers for HS disease severity. The results confirm the rationale for anti-inflammatory therapy targeting NETs in HS.

Uveitis involves a complex interplay of immune cell infiltration and cytokine imbalances, with Th17 cells playing a central role in this process. Th17 cells contribute to disease pathogenesis by promoting inflammation, recruiting additional immune cells, and directly damaging retinal tissues. This review discusses the current knowledge on therapeutic strategies targeting Th17-related cytokines, including cytokine blockade, small molecule inhibitors, and immunomodulatory approaches. Traditionally, Th17-related cytokines have been viewed as pro-inflammatory agents in uveitis. However, emerging research has highlighted the capacity of the Th17 response to express immunoregulatory cytokines, notably IL-10, IL-24, and TGF-β. This suggest that the Th17 response may have a dualistic role that includes immune suppression. In this review, we will discuss this paradoxical nature of Th17 cells in immune regulation and inflammation that they can both promote and mitigate uveitis. We expected that a deeper understanding of these mechanisms is imperative for the innovation of novel therapeutics that could consider the dual role of Th17 response in the pathogenesis of uveitis. By finely tuning the Th17 response to preserve retinal integrity and function, these new treatments could bring significant benefits to patients with uveitis. This review aims to shed light on the complexities of the Th17 response in uveitis and its implications for future therapeutic strategies.

The interleukin (IL)-17 family encompasses six structurally related pro-inflammatory cystine knot proteins, designated as IL-17A to IL-17F. Over the last decades, evidence has pointed to its role as a critical player in the development of inflammatory diseases such as psoriasis (PsO), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA). More specifically, IL-17A and IL-17F are overexpressed in the skin and synovial tissues of patients with these diseases, and recent studies suggest their involvement in promoting inflammation and tissue damage in axSpA and PsA. Bimekizumab is a monoclonal antibody targeting both IL-17A and IL-17F, playing an important role in the treatment of these diseases. This review details the implications of bimekizumab in the therapeutic armamentarium of axSpA and PsA.

Post-stroke depression (PSD) is one of the most common and devastating neuropsychiatric complications in stroke patients, affecting more than one-third of survivors of ischemic stroke (IS). Despite its high incidence, PSD is often overlooked or undertreated in clinical practice, and effective preventive measures and therapeutic interventions remain limited. Although the exact mechanisms of PSD are not fully understood, emerging evidence suggests that the gut microbiota plays a key role in regulating gut-brain communication. This has sparked great interest in the relationship between the microbiota-gut-brain axis (MGBA) and PSD, especially in the context of cerebral ischemia. In addition to the gut microbiota, another important factor is the gut barrier, which acts as a frontline sensor distinguishing between beneficial and harmful microbes, regulating inflammatory responses and immunomodulation. Based on this, this paper proposes a new approach, the microbiota-immune-barrier axis, which is not only closely related to the pathophysiology of IS but may also play a critical role in the occurrence and progression of PSD. This review aims to systematically analyze how the gut microbiota affects the integrity and function of the barrier after IS through inflammatory responses and immunomodulation, leading to the production or exacerbation of depressive symptoms in the context of cerebral ischemia. In addition, we will explore existing technologies that can assess the MGBA and potential therapeutic strategies for PSD, with the hope of providing new insights for future research and clinical interventions.

Mycobacterium abscessus complex pulmonary disease (MABC-PD) is a chronic and often relapsing disease with considerable morbidity, especially among individuals with other chronic pulmonary conditions. A major clinical challenge lies in distinguishing infection-related symptoms from underlying lung disease and identifying reliable prognosticators to guide treatment decisions and monitoring therapeutic response.

To address the gaps in clinically relevant indicators, we profiled whole blood transcriptome and 45 plasma proteins of MABC-PD patients across different disease and treatment phases. Whole blood bulk RNA-sequencing revealed that MABC-PD patients with progressive disease exhibited elevated expression of genes related to innate immune and inflammatory responses, with reduced abundance of genes associated with peripheral T and NK cells. Among the 45 plasma cytokines and chemokines profiled, plasma levels of TNFSF10 were significantly reduced, while IFNγ, interleukin-17F (IL17F) and IL17C were elevated in patients with disease progression, despite the reduced abundance of peripheral T and NK cell-associated genes, suggesting recruitment of activated T cells to infection sites in the lungs during disease progression. Receiver operating characteristic (ROC) curve analysis of IFNγ and IL17F demonstrated strong predictive performance for differentiating patients with disease progression from healthy controls, with AUCs of 0.946 (95% CI 0.829-1.000) and 0.875 (95% CI 0.6699-1), respectively.

These findings provide insights into the immune profiles of MABC-PD patients during disease progression and suggest that T cell-associated cytokines, such as IFNγ and IL17F, could serve as useful biomarkers for identifying those under watchful waiting or post-treatment who are at risk of disease progression, thereby aiding in more timely and targeted therapeutic interventions.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

To evaluated the predictive value of several cerebrospinal fluid (CSF) cytokines in the conversion of clinically isolated syndrome (CIS) patients to neuromyelitis optica spectrum disorder (NMOSD) or multiple sclerosis (MS).

We enrolled 33 CIS patients whose CSF samples were collected during the acute phase of the first onset before immunotherapy. The CSF levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-13, IL-17A, IL-21, IL-23, interferon-γ (IFN-γ) and transforming growth factor beta 1 (TGF-β1) were measured using the human cytokine multiplex assay or ELISA. Patients were seen every 3 to 6 months. Unscheduled visits occur in case of exacerbations. Clinical measures of disease progression were recorded.

The mean follow-up of CIS patients was 23.2 ± 7.9 months. Six patients converted to NMOSD, six patients converted to MS. The CSF IL-21 and IL-6 levels were significantly elevated in CIS patients converted to NMOSD than those who did not. High CSF IL-6 levels are a predictor of conversion to NMOSD in patients with CIS and are associated with a shorter time to conversion. Increased CSF IL-6 levels correlated with CSF WBC count, protein level and IgG index, segment of myelitis, EDSS scores. There was no significant difference in cytokine levels between patients who converted to MS and those who did not.

These findings validate CSF IL-6 as an independent predictive factor for the risk of clinical conversion to NMOSD in CIS. The above CSF cytokines levels in CIS patients can't predict conversion to MS.

Holothuria scabra is one of the most valuable species of sea cucumber owing to its exploitation as a seafood product. This study aims to describe the main molecular and cellular actors in the immunology of this species. First, a detailed description of the immune cells - the cœlomocytes - is provided, highlighting five main cell types including phagocytes, small round cells (SRCs), spherulocytes, fusiform cells, and crystal cells, with a further five subtypes identified using transmission electron microscopy. Cœlomocyte aggregates were also described morphologically, yielding two main types, one comprising three successive maturation stages. A comparison of the concentration and proportion of cell populations was carried out between the two main body fluids, namely the hydrovascular fluid of the Polian vesicle (HF) and the perivisceral fluid of the general cavity (PF), and no clear relation could be highlighted. Next, the cœlomocyte immune response was studied 24 h after lipopolysaccharide (LPS) injection in the two body fluids. Firstly, the fluctuation in cell populations was assessed, and despite a high inter-individual variability, it shows a decrease in the phagocyte proportion and an increase in the SRC proportion. Secondly, the differential gene expression of PF cœlomocytes was studied by de novo RNA-sequencing between LPS-injected and control-injected individuals: 945 genes were differentially expressed, including 673 up-regulated and 272 down-regulated in the LPS-injected individuals. Among these genes, 80 had a presumed function in immunity based on their annotation, covering a wide range of immune mechanisms. Overall, this study reveals a complex immune system at both molecular and cellular levels and constitutes a baseline reference on H. scabra immunity, which may be useful for the development of sustainable aquaculture and provides valuable data for comparative immunology.

Tofacitinib, a first-generation Janus kinase (JAK) 1/3 inhibitor, is commonly used for treating ulcerative colitis and rheumatoid arthritis. However, its role in myasthenia gravis (MG) remains unclear. This study aimed to evaluate the immunomodulatory effects of tofacitinib on experimental autoimmune myasthenia gravis (EAMG) and peripheral blood mononuclear cells (PBMCs) from patients with MG.

Flow cytometry, enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot were used to evaluate the effects of tofacitinib on T helper (Th) cell profiles, humoral immune responses, and the JAK-signal transducer and activator of transcription (STAT) pathway proteins.

In vivo, tofacitinib significantly ameliorated EAMG severity in rats, reducing the proportions of Th1, Th17 and memory B cells, and anti-acetylcholine receptor (AChR) antibodies levels, while increasing the proportions of regulatory T (Treg) cells. In vitro, tofacitinib administration resulted in a significant decrease in the proportions of Th1 and IgG-secreting B cell, and a significant upregulation of Treg cells in mononuclear cells (MNCs) from EAMG rats, which was consistent with findings in PBMCs from MG patients. Further analysis revealed that tofacitinib inhibited CD4+ T cell differentiation into Th1 by decreasing phosphorylated STAT1 levels, while promoting Treg differentiation via increased phosphorylated STAT5 levels in MNCs from EAMG rats.

Tofacitinib modulates Th cell profiles and humoral immune responses by targeting the JAK-STAT pathway, suggesting its potential as a therapeutic candidate for MG. Further clinical studies are warranted to evaluate the efficacy and safety of tofacitinib in MG patients.

Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, characterized by progressive nerve damage driven by chronic hyperglycemia and systemic inflammation. The pathophysiology of DPN is significantly influenced by pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These cytokines promote oxidative stress, vascular dysfunction, and neuronal degeneration by activating important signaling pathways including NF-κB and MAPK. While IL-6 promotes a pro-inflammatory microenvironment, increasing neuronal damage and neuropathic pain, TNF-α and IL-1β worsen Schwann cell failure by compromising axonal support and causing demyelination. Immune cell infiltration and TLR activation increase the inflammatory cascade in DPN, resulting in a persistent neuroinflammatory state that sustains peripheral nerve injury. The main characteristics of DPN are axonal degeneration, decreased neurotrophic support, and Schwann cell dysfunction, which weaken nerve transmission and increase susceptibility to damage. Advanced glycation end-products, TNF-α, and CXCL10 are examples of biomarkers that may be used for early diagnosis and disease progression monitoring. Additionally, crucial molecular targets have been found using proteomic and transcriptome techniques, enabling precision medicine for the treatment of DPN. This review emphasizes the importance of cytokine signaling in the pathogenesis of DPN and how cytokine-targeted treatments might reduce inflammation, restore nerve function, and improve clinical outcomes for diabetic patients.

ZEB1, a zinc-finger E homeobox-binding transcription factor most frequently associated with developmental programs linked to epithelial-mesenchymal transition, has been demonstrated to regulate immune cell function. The study aimed to investigate the expression pattern of ZEB1 in Th17 cells and its colocalization with p-STAT3 in human apical periodontitis lesions.

Thirty-nine human periapical tissues were collected for ex vivo study, including periapical granulomas (PGs, n = 14), radicular cysts (RCs, n = 12), and healthy control tissues (control group, n = 13). Inflammatory infiltration of the lesions was assessed using hematoxylin-eosin staining. The expression of ZEB1 was detected and analyzed by immunohistochemistry. The localization of ZEB1 in Th17 cells and its colocalization with p-STAT3 were assessed using fluorescence colocalization.

ZEB1 expression was significantly higher in PGs and RCs than in the healthy control group; however no significant difference between the two groups was observed. Immunofluorescence analysis revealed that ZEB1 expression was correlated with IL17 and CD4 double-positive cells in human periapical lesions. ZEB1/ p-STAT3 double-positive cells were predominant in RCs and PGs than in the healthy control group.

The expression of ZEB1 was significantly elevated in PGs and RCs, and correlated with Th17 cells and p-STAT3 expression. This study revealed that ZEB1 is a potential player correlated with STAT3 activation and Th17 cells in apical periodontitis pathogenesis.

Activated proinflammatory T helper (Th) cells, including Th1 and Th17 cells, drive immune responses against pathogens and contribute to autoimmune diseases. We show that the expression of inositol polyphosphate multikinase (IPMK), an enzyme essential for inositol phosphate metabolism, is highly induced in Th1 and Th17 subsets. Deletion of IPMK in CD4+ T cells leads to diminished Th1- and Th17-mediated responses, reducing resistance to Leishmania major and attenuating experimental autoimmune encephalomyelitis. IPMK-deficient CD4+ T cells show impaired activation and Th17 differentiation, linked to the decreased activation of Akt, mTOR, and STAT3. Mechanistically, IPMK functions as a phosphatidylinositol 3-kinase to regulate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) production, promoting T cell activation and effector functions. In IPMK-deficient CD4+ T cells, T cell receptor-stimulated PtdIns(3,4,5)P3 generation is abolished by wortmannin, suggesting IPMK acts in a wortmannin-sensitive manner. These findings establish IPMK as a critical regulator of Th1 and Th17 differentiation, underscoring its role in maintaining immune homeostasis.

Advanced therapies (ADT) that encompass biological agents and small molecules have been approved for the treatment of inflammatory bowel disease (IBD), broadening the spectrum of available treatment options. Nevertheless, a substantial proportion of patients fail to achieve satisfactory responses, necessitating surgical intervention. Treatment objectives have evolved beyond clinical remission, reduction of inflammation, and mucosal healing, shifting focus toward enhancing the quality of life, acknowledging the profound impact of IBD on physical and mental well-being.

This comprehensive review describes the current landscape of ADT for IBD, including dual biologic therapy (DBT), which involves the combination of two biologics or a single biologic with a small-molecule compound, as well as considerations surrounding the discontinuation of biologics.

ADT is the standard treatment for moderate to severe IBD, while DBT appears promising for specific subsets of patients, including those with refractory disease or extraintestinal manifestations. However, these approaches may increase the risk of adverse effects, including malignancy. To optimize individualized treatment strategies in patients with refractory IBD, further trials are needed to refine ADT's predictive value, establish DBT's safety and indications, define biologic discontinuation criteria, and evaluate emerging biomarkers, artificial intelligence, and bowel ultrasound in patient management.

In the era of precision medicine, mounting evidence suggests that the time of therapy administration, or chronotherapy, has a great impact on treatment outcomes. Chronotherapy involves planning treatment timing by considering circadian rhythms, which are 24 h oscillations in behavior and physiology driven by synchronized molecular clocks throughout the body. The value of chronotherapy in cancer treatment is currently under investigation, notably in the effects of treatment timing on efficacy and side effects. Immune checkpoint inhibitor (ICI) therapy is a promising cancer treatment. However, many patients still experience disease progression or need to stop the therapy early due to side effects. There is accumulating evidence that the time of day at which ICI therapy is administered can have a substantial effect on ICI efficacy. Thus, it is important to investigate the intersections of circadian rhythms, chronotherapy, and ICI efficacy. In this review, we provide a brief overview of circadian rhythms in the context of immunity and cancer. Additionally, we outline current applications of chronotherapy for cancer treatment. We synthesize the 29 studies conducted to date that examine the impact of time-of-day administration on the efficacy of ICI therapy, its associated side effects, and sex differences in both efficacy and side effects. We also discuss potential mechanisms underlying these observed results. Finally, we highlight the challenges in this area and future directions for research, including the potential for a chronotherapeutic personalized medicine approach that tailors the time of ICI administration to individual patients' circadian rhythms.

Tungsten disulfide (WS2) nanoparticles have emerged in the biomedical field as potential theranostic agents due to their unique properties, including biocompatibility. However, their impact on the immune response remains unexplored. This study aimed to evaluate the effects of inorganic fullerene-like WS2 (IF-WS2) nanostructures on human peripheral blood mononuclear cells (PBMCs) in vitro. The study investigated several parameters to evaluate the effects of IF-WS2 nanoparticles. Cytotoxicity was assessed by measuring cell viability, apoptosis, and necrosis. Internalization of IF-WS2 by PBMCs was analyzed using morphological and flow cytometric techniques. Proliferation was studied in CellTrace Far Red-prestained total PBMCs stimulated with phytohemagglutinin (PHA) and in isolated T cell cultures stimulated with CD3/CD28-coated beads. Additionally, the production of cytokines and chemokines was measured in culture supernatants of total PBMCs and T cells. IF-WS2 nanoparticles were non-cytotoxic up to a concentration of 200 µg/mL. Concentrations ≥25 µg/mL inhibited PHA-stimulated PBMC proliferation but did not affect T cell proliferation. Morphological and flow cytometric analysis demonstrated dose- and time-dependent internalization of IF-WS2 by macrophages. Additionally, IF-WS2 significantly reduced the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8, MCP-1, and GRO-α) in PHA-stimulated PBMCs. Th1, Th17, and Th21 cytokines were downregulated, while Th2, Th9, and T regulatory cytokines were upregulated. In conclusion, this study demonstrated for the first time that pristine IF-WS2 nanoparticles, at non-cytotoxic concentrations, exhibit notable anti-inflammatory and immunomodulatory properties on activated PBMCs in vitro.