Monocytes are circulating immune cells that migrate to inflamed tissues and differentiate into macrophages, where they play a dual role in regulating pro-inflammatory and pro-resolving responses through cytokine and lipid mediator secretion. Platelet-derived microvesicles (PMVs), released during platelet activation, infiltrate inflamed areas and interact with monocytes and macrophages, facilitating the transfer of bioactive contents. While these interactions have been observed, their functional consequences on monocyte/macrophage inflammatory profiles remain poorly understood. In this study, PMVs are shown to be internalized by human THP-1 monocytes. The interaction with THP-1 cells occurs rapidly, with 60 % of cells interacting with PMVs within one hour. When cells are differentiated to M0 and M1 macrophages, interactions with PMVs only peak after 24 h. Interaction of cells with PMVs resulted in an increased capacity to synthesize cyclooxygenase- and lipoxygenase-derived lipid mediators of inflammation, especially in M1 cells. Cytokine production was also influenced in a cell-state-dependent manner. PMVs had no impact on undifferentiated THP-1 cells but enhanced the production of several cytokines in M0 cells as well as IL-23 and IL-6 in M1 macrophages. When stimulated with lipopolysaccharides, PMV-treated M0 macrophages demonstrated elevated production of the anti-inflammatory cytokine IL-10, while M1 macrophages exhibited increased secretion of IL-1β, MCP-1, and IL-6, highlighting an effect on pro-inflammatory cytokine production. These findings reveal that PMVs selectively modulate the inflammatory cytokine and lipid mediator profiles of monocytes and macrophages depending on their differentiation state. This study underscores the role of PMVs as key players in intercellular communication and immune regulation, particularly in the context of inflammation.

Multiple sclerosis (MS) is a group of disorder characterized by aberrant T cell reactivity toward self-antigens with loss of immunological tolerance, resulting in chronic inflammation and tissue damage. CD4+ Th cells can differentiate into Th1, Th2, Th17, and Treg cells in response to a specific class of pathogenic microorganisms and to the cytokine milieu. Here, we found that tyrosine kinase inhibitor sorafenib (Sora), which had been approved by FDA for the treatment of tumor, could suppress pro-inflammatory Th1, Th17 cell differentiation, and promote anti-inflammatory Treg cell polarization. Furthermore, Sora suppressed Th1 and Th17 cell differentiation by STAT4 and TGF-β1 signaling, respectively. In addition, treatment with Sora in mice inhibited Th1, Th17 cell accumulation and promoted Treg cell gather in the brain, thus protecting mice from experimental autoimmune encephalomyelitis (EAE). These results suggest that Sora may be a potential treatment for autoimmune diseases.

Fungi increasingly threaten health globally. Mycoses range from life-threatening, often iatrogenic conditions, to enigmatic syndromes occurring without apparent immunosuppression. Despite some recent advances in antifungal drug development, complementary therapeutic strategies are essential for addressing these opportunistic pathogens. One promising avenue is leveraging host immunity to combat fungal infections; this necessitates deeper understanding of the molecular immunology of human fungal susceptibility to differentiate beneficial versus harmful immunopathological responses. Investigating human models of fungal diseases in natural settings, particularly through genetic immunodeficiencies and ethnographic-specific genetic vulnerabilities, reveals crucial immune pathways essential for fighting various yeasts and molds. This review highlights the diversity in intrinsic fungal susceptibility across individuals and populations, through genetic- and autoantibody-mediated processes, complementing previous principles learned from animal studies and iatrogenic contexts. Improved understanding of human immunity to fungal diseases will facilitate the development of host-directed immunotherapies and targeted public health interventions, paving the way for precision medicine in fungal disease management.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis of unclear etiology. Numerous theories of its underlying pathogenesis have been proposed, including external triggers, neutrophilic dysfunction, complement activation, and autoimmunity, as well as a possible component of underlying genetic susceptibility. This review seeks to synthesize current understanding of the pathogenesis of PG and integrate interactions between the multitude of implicated host immune pathways to guide and inform future directions into the treatment of PG.

Assess the level of adherence to phototherapy and determine what factors influence it.

Cross-sectional.

This study included a convenience sampling of 72 patients with psoriasis undergoing phototherapy. Data were collected through a self-reported questionnaire with sociodemographic variables, the Goldberg Anxiety and Depression Scale, the Short Form Health Survey and the Dermatology Life Quality Index. Adherence to the treatment and its ending was measured through a session record.

A small percentage of the participants demonstrated adequate adherence, and nearly half of them had low adherence. The factors statistically significant and with a negative impact on adherence were as follows: having a partner, experiencing anxiety or depression or using public transportation to get to the hospital. The probability of not adhering to the treatment increased when: patients found it difficult to attend therapy; perceiving their mental and physical health as being worse; experiencing anxiety or depression; having a diagnosed mental illness; being a man; or having had the sickness for an extended period of time.

This study determined the level of adherence to phototherapy and advanced our understanding of this variable. Women exhibited higher levels of adherence compared to men, although they reported worse perceived mental and physical health, and the disease had a higher impact on their life.

Informing phototherapy nurses on the factors that impact treatment adherence may help to increase the treatment compliance, which may improve psoriasis patients' clinical symptoms.

Increase the body of knowledge about the treatment that phototherapy nurses administer.

STORBE guidelines.

No patient or public contribution.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, with varying clinical phenotypes and prognoses. Regulatory T cells (Tregs), particularly CD4+FOXP3+ T cell subpopulations, are crucial in modulating immune responses. This study investigates the distribution of two CD4+FOXP3+ T cell subpopulations in bronchoalveolar lavage fluid (BALF) from COPD patients and their association with disease phenotypes and prognosis. Patients were classified into Type A (lower frequencies of inflammatory FOXP3lo T cells) and Type B (higher frequencies of inflammatory FOXP3lo T cells). Type B COPD patients, who demonstrated more severe emphysema, heightened inflammatory responses, faster lung function decline, and more pronounced osteoporosis, showed a significant increase in FOXP3lo non-suppressive T cells. In contrast, Type A patients exhibited a higher proportion of FOXP3hi Treg cells, which correlated with milder disease phenotypes. The distinct distribution of CD4+FOXP3+ T cell subpopulations provides insights into the progression of COPD and suggests that these cells could serve as potential biomarkers for disease severity and prognosis. Further research may offer new therapeutic avenues by targeting these Treg subpopulations in COPD management.

Human pyoderma gangrenosum (hPG) is a rare, non-infectious neutrophilic dermatosis characterized by painful, necrotic ulcers with violaceous borders. Research on hPG is limited by minimal existing animal models, the sole being a pharmacologically induced murine model. Few cases of canine pyoderma gangrenosum (cPG) have been published, and dogs are genetically closer to humans than are mice, making them a potentially valuable model of hPG. We aimed to characterize all published cPG cases and compare their presentation to that of hPG. A Google Scholar, PubMed, and Embase search of "canine AND pyoderma gangrenosum" was conducted in August 2024, with seven case reports, two case series, and two veterinarian-sourced cases ultimately reviewed. Of the 31 analyzed cPG cases, 30 presented with skin ulcers at multiple sites, the most common being the trunk (64.5%), paws (41.9%), and limbs (32.3%), mirroring the typical localization of hPG on the lower extremities, back, and abdomen. The average age of cPG presentation was 7.8 +/- 3.7 years (range: 0.25-14.5 years). Dogs reflected hPG comorbidities, with 16.1% presenting with gastrointestinal pathologies, 6.5% with arthritis, and 6.5% with hematologic disorders. Dogs were responsive to medications frequently employed in hPG-prednisone/prednisolone (80.6%) as initial therapy, and cyclosporine (77.4%) as maintenance therapy. Overall, cPG resembles hPG in affected anatomic sites, comorbidities, and therapeutic response. It offers a representative, spontaneously occurring hPG animal model alternative to the existing murine model. Future studies are necessary to reproduce cPG to further investigate disease pathophysiology.

Group B Streptococcus is a significant cause of early-onset disease in term newborns, with a global incidence of 0.41/1000 live births. Intrapartum antibiotic prophylaxis (IAP) has reduced EOD incidence by over 80%, but concerns exist about its impact on the neonatal gut microbiome and potential long-term health effects.

This single center study examines the effects of IAP on the fecal infant microbiome in the first year of age and on the T cell phenotype in the first days after birth among 22 infants receiving IAP with penicillin due to maternal GBS colonization and 26 infants not exposed to IAP. The fecal microbiome was analyzed at birth, one month and one year of age through 16S rRNA gene sequencing. Additionally, a T cell phenotyping of peripheral blood was performed between the second and fifth day of age.

At one month, IAP exposed infants had a significantly lower relative abundance of Bifidobacterium longum in fecal samples, an effect which was sustained at one year. In IAP exposed infants we found a proinflammatory T-helper cell profile, characterized by higher IL-17A, RORgt, and TGF-b expression.

This study proposes a sustained impact of IAP on the neonatal microbiome and T cell repertoire.

Fungal infections are a major source of morbidity and mortality in people with compromised immune systems, such as those with human immunodeficiency virus, cancer, organ transplant recipients, and patients undergoing chemotherapy in healthcare settings. According to a recent World Health Organization (WHO) fungal priority pathogens list, Cryptococcus spp., Candida spp., Aspergillus spp., and Candida auris cause severe invasive infections in human. These opportunistic pathogens cause a significant number of mycoses, which affect over a billion people annually. Around two million infections can be fatal, especially for those with compromised immune systems. To diagnose and treat mycoses, we need to understand the complex interactions between the fungus and the host during pathogenesis, the virulence-causing traits of the fungus, and how the host fights infection through the immune system. Although several antifungal drugs are available against fungal infections, their effectiveness is highly variable, with adverse effects. In addition, the increasing resistance to traditional antifungal treatments poses serious risks to the healthcare industry. Therefore, new therapeutic strategies are required to combat these potentially fatal fungal infections. Nanostructure-based formulations can improve the therapeutic efficacy of conventional medications by broadening their activities, decreasing toxicity, enhancing bioactivity, and improving biodistribution. The review highlights host and fungus interaction and how nanoformulations can be targeted against fungal infections.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU), significantly impacts quality of life. Despite significant advances in the management of the conditions, responses to treatments vary greatly, and this is due partly to our natural genetic variation. Here we will review the evidence for whether single nucleotide polymorphisms (SNPs) have the potential to guide treatment decisions for people with IBD. We will first consider SNPs that exhibit strong associations with IBD pathogenesis and their relevance to epithelial barrier integrity, cytokine production, and immune system function. Then, we will cover those SNPs implicated in altering response to our various current IBD therapeutics, including the recently implemented drugs ustekinumab and tofacitinib. Finally, we will explore lesser-known SNPs that exhibit complex relationships with the disease and which may be undervalued as pharmacogenetic tools. Overall, it will be demonstrated that SNPs associated with IBD pathology are largely distinct from those predicting response to treatments and that new discoveries of clinically useful tools can be expected from therapy-focused investigations. Given the growing list of treatments available, we argue that beneficial personalization of treatments based on SNPs is still underutilized.

Evaluate guselkumab efficacy, an anti-interleukin-23p19-subunit antibody, in patients with active psoriatic arthritis (PsA) and inadequate response to 1 or 2 tumour necrosis factor inhibitors (TNFi-IR), utilizing composite indices assessing disease activity across disease domains.

In the Phase IIIb COSMOS trial, 285 adults with TNFi-IR PsA were randomized (2:1) to receive guselkumab 100 mg or placebo at Week (W)0, W4, then every 8 weeks through W44. Patients receiving placebo crossed over to guselkumab at W24. In this post hoc analysis, composite indices evaluated included the Disease Activity Index for Psoriatic Arthritis (DAPSA), Disease Activity Score 28 (DAS28), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Disease Activity Score (PASDAS), GRAPPA Composite score (GRACE), modified Composite Psoriatic Disease Activity Index (mCPDAI), minimal disease activity (MDA), and very low disease activity (VLDA). Through W24, treatment failure rules were applied. Through W48, non-responder imputation was used for missing data.

Greater proportions of guselkumab- than placebo-randomized patients achieved composite index endpoints relating to low disease activity (LDA; 14.8-52.4% vs 3.1-28.1%) or remission (3.7-5.3% vs 0.0-2.1%) at W24. Among guselkumab-randomized patients, LDA rates increased to W48 (DAPSA, 44.4%; DAS28, 47.8%; PASDAS, 34.4%; GRACE, 33.3%; mCPDAI, 40.2%), and 27.0% and 64.0% achieved MDA and a PsARC response, respectively. In the placebo→guselkumab crossover group, W48 response rates were similar to the guselkumab-randomized group.

Guselkumab treatment provided substantial benefits across multiple disease domains, with increasing proportions of patients achieving LDA/remission over 1 year, highlighting the effectiveness of guselkumab despite previous inadequate response to TNFi.

Leishmania spp. infections pose a significant global health challenge, affecting approximately 1 billion people across more than 88 endemic countries. This unicellular, obligate intracellular parasite causes a spectrum of diseases, ranging from localized cutaneous lesions to systemic visceral infections. Despite advancements in modern medicine and increased understanding of the parasite's etiology and associated diseases, treatment options remain limited to pentavalent antimonials, liposomal amphotericin B, and miltefosine. A deeper understanding of the interactions between immune and non-immune cells involved in the clearance of Leishmania spp. infections could uncover novel therapeutic strategies for this debilitating disease. This review highlights recent progress in elucidating how various cell types contribute to the regulation and resolution of Leishmania spp. infections.

Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease leading to eventual neurodegeneration. There is a strong interest in using blood biomarkers to detect the disease onset and monitor disease progression in MS. One such biomarker is neurofilament light chain (NfL) that reflects axonal damage or neurodegeneration. Proinflammatory cytokines involved in T-helper 17 (Th17) lymphocyte signaling are potential blood biomarkers of neuroinflammation.

We induced experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, in female C57BL/6 mice and measured the progression of EAE using a clinical score. We collected blood from EAE mice on the post-immunization days 7, 10, 16, or 22 and measured NfL concentrations using single molecule array (SIMOA) technology. We also measured concentrations of cytokines related to Th17 using xMAP immune assay technology (Luminex) from the same mice.

We found that the concentration of NfL began to rise at the onset of clinical symptoms on the post-immunization day 10 and peaked on day 16, closely correlating with the clinical score. However, the concentrations of several proinflammatory cytokines, including IFN-γ, IL-6, IL-17A, IL-22, and TNF-α, were already elevated even before the onset of the clinical symptoms and did not correlate positively with the clinical scores.

Our results confirmed the utility of NfL as a blood biomarker for disease progression in MS. The elevation of multiple proinflammatory cytokines concentrations in the blood of the same EAE mice in the presymptomatic stage suggested that blood biomarkers for neuroinflammation increased before blood biomarkers for neurodegeneration during the disease course in EAE.

Thyroid hormone homeostasis during pregnancy is crucial for proper neurodevelopment and cognitive capacity during adulthood. Accumulating evidence reveals that gestational hypothyroxinemia (HTX) modulates the immune response of the adult offspring.

In the present study, adult mice gestated in HTX and their euthyroid counterparts were induced with a mild form of experimental autoimmune encephalomyelitis (EAE), a widespread model of multiple sclerosis, and analyzed at baseline and 7 days after EAE induction.

Levels of circulating IL-17 were significantly lower in mice gestated in HTX at both timepoints, while circulating IFN-γ was significantly higher only in mice gestated in HTX, 7 days after EAE induction. A significant increase in type 1 innate lymphoid cells (ILC1) was found only in mice gestated in HTX 7 days after EAE induction, while type 3 innate lymphoid cells (ILC3) populations showed no variation. Interestingly, a significant increase of Th17 CD4+ cells was found only in mice of euthyroid gestation, 7 days after EAE induction.

These results highlight the repercussions of thyroid hormone impairment in utero at adult ages while dissecting on the pathogenesis of EAE in terms of Th1/Th17 balance from an innate immune perspective. These findings contribute to the advancement of our comprehension of the presymptomatic stage of EAE, unveiling new paths for basic and translational research in the field of neuroinflammation.

The ductular reaction (DR) is a dynamic adaptive cellular response within the liver, triggered by various hepatic insults and characterized by an expansion of dysmorphic biliary epithelial cells and liver progenitors. This complex response presents a dual role, playing a pivotal function in liver regeneration but, paradoxically, contributing to the progression of liver diseases, depending upon specific contextual factors and signaling pathways involved. This comprehensive review aims to offer a holistic perspective on the DR, focusing into its intricate cellular and molecular mechanisms, highlighting its pathological significance, and exploring its potential therapeutic implications. An up-to-date understanding of the DR in the context of different liver injuries is provided, analyzing its contributions to liver regeneration, inflammation, fibrosis, and ultimately carcinogenesis. Moreover, the review highlights the role of multiple microenvironmental factors, including the influence of extracellular matrix, tissue mechanics and the interplay with the intricate hepatic cell ecosystem in shaping the DR's regulation. Finally, in vitro and in vivo experimental models of the DR will be discussed, providing insights into how researchers can study and manipulate this critical cellular response. By comprehensively addressing the multifaceted nature of the DR, this review contributes to a more profound understanding of its pathophysiological role in liver diseases, thus offering potential therapeutic avenues for hepatic disorders and improving patient outcomes.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to help resolve inflammation through generation of anti-inflammatory eicosanoids and specialized pro-resolving mediators, including resolvins, protectins, and maresins. Through binding to the GPR120/FFAR4 receptor, their beneficial effects result from phospholipid membrane remodeling, impairment of inflammatory signaling molecules clustering, subsequent inhibition of NF-κB and inflammasome activation, and a reduction in oxidative stress. Obesity, a chronic inflammatory disease that contributes to metabolic disorders, is alleviated by n-3 PUFAs. In the adipose tissue (AT) of individuals with obesity, n-3 PUFAs counteract hypoxia, inhibit immune cell infiltration and AT inflammation, improve insulin sensitivity, and reduce fat mass. Beyond AT, n-3 PUFAs also alleviate other metabolic disorders such as metabolic-associated steatotic liver disease (MASLD), gut dysbiosis, and/or renal dysfunction. In cardiovascular disease (CVD), they are mainly recommended as a secondary prevention for patients with coronary heart disease risks. This review provides an in-depth analysis of the benefits of n-3 PUFAs in obesity and related metabolic diseases, examining both the mechanistic and clinical aspects. Additionally, it also explores the effects of n-3 PUFAs in obesity-related chronic inflammatory conditions, including inflammatory bowel disease, psoriasis, rheumatoid arthritis, osteoarthritis, and multiple sclerosis, by targeting specific pathophysiological mechanisms. Clinical applications and limitations of n-3 PUFAs are discussed based on findings from human clinical trials.

Periodontitis is a common dysbiotic bacteria-induced inflammatory disease characterized by alveolar bone resorption, leading to tooth loss. Interleukin-17 (IL-17) is a critical cytokine with dual roles in periodontium, which exerts the function of host defense, including neutrophil recruitment, phagocytosis, and mucosal immunity. However, excessive expression of IL-17 causes persistent chronic inflammation, local tissue breakdown, and bone loss. This review highlights the protective and pathological functions of IL-17 on immunity and bone homeostasis in inflammatory bone-related diseases. We also provide the latest findings with IL-17 knockout mice in periodontitis and highlight complex immune responses under various experimental models. This may provide a critical perception of inflammatory bone-related disease management using an immune-modulating strategy.

GWAS have identified tyrosine kinase 2 (TYK2) variants in multiple inflammatory disorders, specifically a protective hypomorphic TYK2 allele (P1104A) in multiple sclerosis (MS). Impaired TYK2 signaling within the central nervous system (CNS) may impart the protective effects of TYK2 P1104A allele in MS. We deployed brain-penetrant TYK2 inhibitors (cTYK2i) alongside the peripherally restricted TYK2 inhibitor (pTYK2i; BMS-986165) to untangle the contributions of central TYK2 inhibition in diverse models of neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines in experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated in cTYK2i-treated EAE spinal cords and circulating neurofilament light (NfL) was reduced in plasma and cerebral spinal fluid (CSF). Additionally, cTYK2i was protective in an antibody-mediated mouse model of primary progressive MS (PPMS). Finally, we demonstrate TYK2 inhibition has a robust impact on a unique subset of activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes (IRRA). The data presented herein identify a key role for CNS TYK2 signaling in regulating neuroinflammation and solidify TYK2 as a potential therapeutic target for MS.

There are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD.

We aimed to assess the safety and tolerability of guselkumab in patients with ALD.

This phase-1 dose-escalation study included patients with ≥ 2 DSM-5 criteria for alcohol use disorder, significant steatosis (MRI-PDFF ≥ 8%) and MRE < 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose-limiting toxicity.

We enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49-61] years. The median MRI-PDFF and MRE were 18.4% [IQR 8.4%-34.0%] and 2.5 [2.2-2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)-17, IL-23, IL-1b and TNF-α in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT-C: 6 [3-7] vs. 5 [1-6], p = 0.023).

Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.

Psoriasis is a chronic inflammatory skin autoimmune disease. Th17 cells, when pathologically activated, significantly contribute to the progression of psoriasis. The symptoms of this skin condition could be notably alleviated by targeting and suppressing the activity of these cells. Retinoic acid receptor-associated orphan nuclear hormone receptor γ-t (RORγt), a critical transcription factor in Th17 cells, emerges as a promising therapeutic target for autoimmune conditions which are mediated by the dysregulation of these cells. In this study, we designed and synthesised a series of artemisinin analogues based on the chemical structure of artemisinin, and screened 3 compounds, QHS-1, QHS-2, and QHS-3, with better inhibition efficiency of RORγt activity. We found that each of the three artemisinin analogues were demonstrated efficacy in curbing IMQ-induced skin inflammation and the abnormal proliferation of keratinocytes within the BALB/c mouse model of psoriasis. Our findings indicate that the three artemisinin analogues not only effectively mitigated skin inflammation and the abnormal proliferation of keratinocytes in the IMQ-induced psoriasis model of BALB/c mice but also curtailed the infiltration of immune cells and the production of pro-inflammatory cytokines in the dermis. Furthermore, these compounds modulated the cytokine expression profiles within Th17 cells. They exerted a suppressive effect on the activity of Th17 cells by targeting RORγt, thereby dampening the inflammatory response in the dorsal skin of the mice. This inhibition led to a reduction in the pathological proliferation of keratinocytes. In conclusion, our research underscores the promising therapeutic potential of artemisinin analogues in the treatment of psoriasis, offering a slate of candidate compounds which could pave the way for novel drug development in this field.

Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by transporting functional molecules between donor cells and recipient cells, thereby regulating biological processes, such as immune responses. miR-451a, an immune regulatory microRNA, is highly abundant in circulating EVs; however, its precise physiological significance remains to be fully elucidated. Here, we demonstrate that miR-451a deficiency exacerbates delayed-type hypersensitivity (DTH) in mice. Notably, miR-451a knockout resulted in a significant increase in the number of interleukin (IL)-17A-expressing T helper 17 and γδ T cells infiltrating DTH-induced ear lesions. miR-451a deficiency also increased the number of γδ T cells in the secondary lymphoid tissues. Comprehensive analyses revealed that miR-451 deficiency promoted the expression of Rorc and γδ T cell-related genes following sensitization with allergens. Moreover, intravenous administration of wild-type EVs to miR-451a knockout mice increased cellular miR-451a levels in tissues and significantly attenuated the severity of DTH. Furthermore, synthetic lipid nanoparticles encapsulating miR-451a effectively mitigated DTH. Our findings indicate the importance of circulating miR-451a in the proliferation of γδ T cells and highlight the therapeutic potential of lipid nanoparticle-based microRNA delivery platforms for interventions in immune-related diseases.

Stem-like T cells selectively contribute to autoimmunity, but the activities that promote their pathogenicity are incompletely understood. Here, we identify the transcription coregulator OCA-B as a driver of the pathogenic maturation of stem-like CD4 + T cell to promote autoimmune demyelination. Using two human multiple sclerosis (MS) datasets, we show that POU2AF1 , the gene encoding OCA-B, is elevated in CD4 + T cells from MS patients. We show that T cell-intrinsic OCA-B loss protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to viral CNS infection. In EAE models driven by antigen reencounter, OCA-B deletion nearly eliminates CNS infiltration, proinflammatory cytokine production and clinical disease. OCA-B-expressing CD4 + T cells of mice primed with autoantigen express an encephalitogenic gene program and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B loss protects mice specifically at relapse. During remission, OCA-B promotes the expression of Tcf7 , Slamf6 , and Sell in proliferating CNS T cell populations. At relapse timepoints, OCA-B loss results in both the accumulation of an immunomodulatory CD4 + T cell population expressing Ccr9 and Bach2 , and loss of pro-inflammatory gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic CD4 + T cells.

Interleukin (IL)-17, a pro-inflammatory cytokine, plays a pivotal role in immune regulation by bridging innate and adaptive responses. Beyond its canonical involvement in T helper-17 cells-mediated immunity, IL-17 contributes significantly to the pathogenesis of systemic autoinflammatory diseases (SAIDs) including Familial Mediterranean Fever (FMF), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-associated autoinflammatory diseases, and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Dysregulated IL-17 signaling drives inflammasome activation, neutrophil recruitment, and chronic tissue inflammation. IL-17 inhibitors have demonstrated efficacy in refractory SAIDs, though challenges such as increased infection risks, paradoxical inflammatory reactions, and uncertainties regarding long-term safety persist. Currently, there is insufficient data to support the use of IL-17 inhibitors as first-line treatments, and their role in managing SAIDs is yet to be fully defined. This review highlights the mechanistic role of IL-17 in SAIDs and emerging therapeutic strategies, including IL-17-targeted monotherapies and combination approaches with IL-1 or tumor necrosis factor (TNF) inhibitors. Future research should focus on biomarker development, combination therapies, and long-term studies to optimize the safety and efficacy of IL-17-targeted therapies in SAIDs.

Maternal vaccination is essential for safeguarding both mother and foetus from infectious diseases. This study investigated the immunogenicity and efficacy of a maternal ORF-B2L genetic vaccine in a pregnant rat model, focusing on maternal-neonatal immune modulation, placental and neonatal spleen transcriptomics and the underlying mechanisms contributing to neonatal immune development. Female rats received intramuscular injections of either a gene vaccine (GV) containing 200 μg of recombinant ORF-B2L DNA and 50 μg of a subunit protein or an empty plasmid as a control. Results showed significantly higher levels of specific anti-B2L antibodies and Th1 and Th2 cytokine levels in both maternal and neonatal sera from the GV group compared to the control group (p < 0.05). Transcriptome analysis identified 1295 differentially expressed genes (DEGs) in the placenta and 998 DEGs in the neonatal spleen, with upregulated pathways associated with immune cell recruitment, cytokine signalling and hormone regulation in the GV group. Notably, upregulated DEGs such as TLR4, ESR1 and various cytokine/chemokine-related genes in the placenta suggest enhanced immune regulation and foetal protection. In the neonatal spleen, increased expression of IL-1β, IL-6, IL-10 and CD69 indicates enhanced T and B cell development and pathogen defence. The upregulation of IL-1β suggests a Th1 response, while elevated IL-10 indicates a potential Th2-biased immunity, reflecting a balanced Th1/Th2 response that is crucial for effective adaptive immunity. Overall, maternal ORF-B2L genetic vaccination induces a robust immune response, enhancing maternal-foetal protection and shaping neonatal immune responses, offering valuable insights for optimizing maternal vaccination strategies.

IL-23 signaling plays a key role in the pathogenesis of chronic inflammatory and infectious diseases, yet the cellular targets and signaling pathways affected by this cytokine remain poorly understood. We show that IL-23 receptors are expressed on the large majority of human mucosal-associated invariant T (MAIT), but not of conventional T cells. Protein and transcriptional profiling at the population and single cell level demonstrates that stimulation with IL-23 or the structurally related cytokine IL-12 drives distinct functional profiles, revealing a high level of plasticity of MAIT cells. IL-23, in particular, affects key molecules and pathways related to autoimmunity and cytotoxic functions. Integrated analysis of transcriptomes and chromatin accessibility, supported by CRISPR-Cas9 mediated deletion, shows that AP-1 transcription factors constitute a key regulatory node of the IL-23 pathway in MAIT cells. In conclusion, our findings indicate that MAIT cells are key mediators of IL-23 functions in immunity to infections and chronic inflammatory diseases.

The nonclassical population of Th1-polarized Th17 lymphocytes (Th17.1/ex-Th17) is currently in the focus of researchers' attention. These cells possess a unique proinflammatory potential and ability to penetrate blood-tissue barriers and play a key role in the pathogenesis of many inflammatory diseases, primarily autoimmune ones. Th1-polarized Th17 lymphocytes prevail in the autoimmune lesion foci and are considered to be a promising therapeutic target in these pathologies. At the same time, recent studies have shown another distinctive feature of Th1-polarized Th17 - their selective resistance to glucocorticoids. Since glucocorticoids are the first-line drugs for the treatment of the autoimmune disease exacerbation, understanding the causes of this phenomenon is crucial for predicting patients' response to therapy and improving the treatment effectiveness. This review analyzes the mechanisms of drug resistance of Th1-polarized Th17 cells, compares these mechanisms with those typical of nonpathogenic classical Th17 cells, and discusses the role of glucocorticoid resistance in the body's response to glucocorticoid therapy.

Inflammatory bowel disease (IBD) and colorectal cancer (CRC), as two of the major human intestinal diseases, provide challenges for the medical field. Suppressor of cytokine signaling 3 (SOCS3), a protein molecule that negatively regulates cytokine signaling through multiple pathways, is involved in the regulation of various inflammatory diseases and tumors. In IBD, SOCS3 acts on a variety of cells to repair mucosal damage and balance the immune response, including epithelial cells, macrophages, dendritic cells, neutrophils, and T cells. In CRC, SOCS3 is inextricably linked to tumor cell proliferation, invasion, metastasis, and drug resistance. Therefore, it is crucial to systematically investigate the pathogenic involvement of SOCS3 in IBD and CRC. This article reviews the mechanisms and pathways by which SOCS3 is involved in the inhibition of IBD and the mitigation of CRC, and details the therapeutic options for targeting SOCS3.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.

Multiple Sclerosis (MS) is a complex auto-inflammatory disease affecting the brain and spinal cord, which results in axonal de-myelination and symptoms including fatigue, pain, and difficulties with vision and mobility. The involvement of the immune system in the pathology of MS is well established, particularly the adaptive T cell response, and there has been a particular focus on the IL-17-producing subset of Th17 cells and their role in driving disease. However, the importance of innate immune cells has not been so well characterized. Here we focussed on neutrophils, which are innate immune cells and rapid responders to inflammation, and which have recently been linked to other chronic autoimmune conditions. Multiple strands of evidence in patients with MS and in mice with the experimental autoimmune encephalomyelitis MS model suggest neutrophils may play a role in driving MS inflammation. Here, we performed proteomic analysis on neutrophils from patients with MS and healthy donors, revealing striking differences. In particular, granule proteins were significantly more abundant in the MS neutrophils compared to the healthy controls, with a particular overabundance of proteins in primary and secondary granules. In addition, members of the MAVS signalling pathway were differently regulated compared to healthy donor cells. Finally, we find that MS neutrophils do not suppress T cell activation equivalently to healthy neutrophils, and in particular are unable to suppress expression of CD161 on the T cells, indicative of a suppression of Th17 differentiation. We propose that neutrophil dysregulation in MS may contribute to dysfunctional T cell responses.

Multiple sclerosis (MS) is a highly disabling chronic neurological condition affecting young adults. Inflammation, demyelination, and axonal damage are key pathological features of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Our previous work demonstrated that inhibiting spermine oxidase (SMOX) with MDL72527, a selective irreversible pharmacological inhibitor, significantly reduced clinical symptoms, retinal ganglion cell (RGC) loss, and optic nerve inflammation in EAE mice. The present study explored the broader therapeutic potential of SMOX inhibition, focusing on myelin preservation, axonal integrity, and visual function in the EAE model. Electron microscopy of optic nerve cross-sections showed significant preservation of myelin thickness and axonal integrity due to SMOX inhibition. The quantitative assessment showed that g-ratio and axon count metrics were significantly improved in MDL72527-treated EAE mice compared to their vehicle-treated counterparts. Immunofluorescence studies confirmed these findings, showing increased preservation of myelin and axonal proteins in MDL72527-treated EAE mice compared to the vehicle-treated group. Functional assessment studies (Electroretinography) demonstrated significant improvement in RGC function and axonal conduction in EAE mice treated with MDL72527. Furthermore, SMOX inhibition downregulated the expression of galectin3 (Gal3), a mediator of neuroinflammation, indicating Gal3's role in SMOX-mediated neuroprotection. This study provides compelling evidence for the potential of SMOX inhibition as a therapeutic strategy in multiple sclerosis and other demyelinating disorders.

Interleukin-23 (IL-23) inhibitors and the IL-12/23 inhibitor ustekinumab constitute a pivotal class of therapeutic agents employed in the clinical management of Psoriasis, a chronic immune-mediated skin disorder. Notwithstanding their therapeutic efficacy, concerns have arisen due to the emergence of multiple adverse events (AEs) associated with their usage. This study aims to provide a comprehensive examination of the distribution and characteristics of these AEs concerning IL-23 and IL-12/23 inhibitors, with a specific focus on guselkumab, tildrakizumab, risankizumab, and ustekinumab.

In this research endeavor, we conducted an extensive analysis of data extracted from the FDA Adverse Event Reporting System (FAERS), spanning the timeframe from January 1, 2014, to September 30, 2022. To identify potential signals of AEs, we rigorously applied disproportionality analysis, utilizing both reporting odds ratio (ROR) and information component (IC) metrics. A signal was considered present when the lower limit of the 95% confidence interval (CI) for ROR (ROR025) exceeded one or when IC (IC025) surpassed zero, with a minimum requirement of three or more reported cases.

Our investigation encompassed a substantial dataset, comprising a total of 41,408,408 reports detailing drug-AE associations and involving 13,271,168 individuals. Among these, 704, 13,164, and 11,399 patients were identified as users of the IL-23 inhibitors tildrakizumab, guselkumab, and risankizumab, respectively, while 62,853 patients were identified as users of the IL-12/23 inhibitor ustekinumab. The analysis revealed the presence of 8, 20, 107, and 115 signals for these respective drugs. Significantly, the System Organ Class (SOC) exhibiting the highest incidence was "infections and infestations," with documented occurrences in tildrakizumab (6/8), guselkumab (5/20), ustekinumab (50/107), and risankizumab (25/115).

Our pharmacovigilance analysis has brought to light a substantial frequency of AEs linked to IL-23 and IL-12/23 inhibitors. These findings underscore the pivotal role of IL-23 and IL-12/23 inhibitors in modulating immune function and raise concerns regarding their potential to heighten susceptibility to infections and malignancies. However, limitations inherent to the FAERS database, including underreporting, lack of denominator data, potential duplicate records, and inability to confirm causality, should be acknowledged of particular significance is risankizumab, which, despite having fewer reported cases and a later market introduction compared to ustekinumab, exhibited a higher incidence of AEs. These results emphasize the necessity for ongoing vigilance, further investigation, and a reevaluation of the safety profile of IL-23 and IL-12/23 inhibitors in the clinical management of Psoriasis.

Multiple genetic associations suggest a causative relationship between Th17-related genes coding for proteins, such as IL-17A, IL-23 and STAT3, and psoriasis. Further support for this link comes from the findings that neutralizing antibodies directed against IL-17A, IL-17RA and IL-23 are efficacious in diseases like psoriasis, psoriatic arthritis and ankylosing spondylitis. RORγt is a centrally positioned transcription factor driving Th17 polarization and cytokine secretion and modulation of RORγt may thus provide additional benefit to patients. However, RORγt also plays a role in the normal development of T cells in the thymus and genetic disruption of RORγt in the mouse leads to the development of lymphoma originating in the thymus. Whilst it is not established that down-regulation of RORγt activity would lead to the same consequence in humans, further understanding of the thymus effects is desirable to support progress of this target as a potential treatment of Th17-driven disease. Herein we present the characterisation of recently disclosed RORγt inverse agonists demonstrating target engagement and efficacy in vitro and in vivo against Th17 endpoints but requiring higher concentrations in vitro to affect thymocyte apoptosis.

Acute upper respiratory tract infections are a major public health issue, with uncontrolled inflammation triggered by upper respiratory viruses being a significant cause of patient deterioration or death. This study focuses on the Janus kinase-signal transducer and activator of transcription Rho-associated coiled-coil containing protein kinase (JAK-STAT-ROCK) signaling pathway, providing an in-depth analysis of the interplay between uncontrolled inflammation after upper respiratory tract infections and the development of neurodegenerative diseases. It offers a conceptual framework for understanding the lung-brain-related immune responses and potential interactions. The relationship between the ROCK-JAK-STAT signaling pathway and inflammatory immunity is a complex and multi-layered research area and exploring potential common targets could open new avenues for the prevention and treatment of related inflammation.

Behçet's disease is a chronic inflammatory condition that affects multiple organs and systems. It is characterized by recurrent oral and genital ulcers. A previous study reported that the IL-17A inhibitor secukinumab can improve the skin and mucosal manifestations in patients with refractory Behçet's disease. Additionally, secukinumab has been shown to effectively improve neurological symptoms when administered for Behçet's disease. However, we report a case where Behçet's disease occurred after the treatment of psoriasis with the IL-17A inhibitor ixekizumab. To summarize its clinical characteristics and treatment experience, we consulted relevant domestic and international literature and conducted a literature review. We concluded that anti-IL-17A treatment may lead to the development of Behçet's disease. The reported cases are more likely to occur in middle-aged men with varying onset times. The main manifestations include oral and vulvar mucosal ulcers. Furthermore, the gut microbiota may be involved in paradoxical Behçet's disease.

Severe asthma is a critical condition for patients with asthma, characterized by frequent exacerbations, decreased pulmonary function, and unstable symptoms related to asthma. Consequently, the administration of systemic corticosteroids, which cause secondary damage because of their adverse effects, is considered. Recently, several types of molecular-targeted biological therapies have become available for patients with severe asthma, and they have a capacity to improve the pathophysiology of severe asthma. However, several clinical reports indicate that the effects differ depending on the biological targets of asthma in individual patients. In this review, the molecular mechanisms and clinical impact of biologic therapies in severe asthma are described. In addition, molecules targeted by possible future biologics are also addressed. Better understanding of the mechanistic basis for the role of biologics in severe asthma could lead to new therapeutic options for these patients.

Limited knowledge exists regarding biomarkers that predict treatment response in Lupus nephritis (LN). We aimed to identify potential molecular biomarkers to predict treatment response in patients with LN. We enrolled 66 patients with active LN who underwent renal biopsy upon enrollment. Serum and urine samples were collected longitudinally, and we measured 12 biomarkers in each sample using a multiplex immunofluorescence assay. These biomarkers included monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein 10 (IP-10), interferon-γ (IFN-γ), interleukin 6 (IL-6), interleukin 16 (IL-16), interleukin 17 (IL-17), interleukin 23 (IL-23), tumor necrosis factor receptor II (TNF-RII), vascular cell adhesion molecule 1 (VCAM-1), retinol-binding protein 4 (RBP 4), vitamin D binding protein (VDBP), and neutrophil gelatinase-associated lipocalin (NGAL). Patients were categorized into two groups based on their 1-year treatment response to Mycophenolate mofetil (MMF)-based therapy: 50 responders and 16 non-responders. Only urine IL-17 (uIL-17) showed baseline level differences between the two groups, with higher in responders. In ROC curve analyses assessing the predictive performance of biomarkers, baseline uIL-17 and changes in uIL-6 and uIL-23 levels at 3 months could predict the 1-year treatment response, showing AUC values of 0.70 (95% CI 0.54-0.87), 0.70 (0.54-0.86), and 0.71 (0.57-0.85), respectively. Combining uIL-6 and uIL-23 into a model improved predictability, achieving an AUC of 0.75 (0.61-0.90). Baseline uIL-17 levels and early changes in uIL-6 and uIL-23 could serve as potential biomarkers to predict 1-year treatment response in lupus nephritis patients receiving MMF-based therapy.

Multiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits. This study aims to examine whether peripheral production of Myelin Basic Protein (MBP)-driven cytokine responses mediate the aging-associated decline in MS inflammatory DA.

We included the clinical data of 669 adult pwMS between 2017 and 2022 who enrolled in a clinic-based prospective cohort. From a subset of 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50μg/ml of MBP (or heat-killed Candida) for 24 hours. We assayed cell culture supernatants for interleukin 17 (IL-17) and interferon gamma (IFN-γ) using Enzyme-Linked Immunosorbent Assay and a subset of the supernatant samples using a commercial human cytokine/chemokine array. We examined the associations between age and annualized relapse rate (ARR) as well as between age and MBP-stimulated cytokine production (by cultured PBMC) using covariate-adjusted linear regressions. We performed mediation analyses to determine the extent to which MBP-driven cytokine response drives the association between age and ARR.

Among 669 pwMS (mean age 51.7±12.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (β=-0.003, p<0.001). Among the subgroup of 80 pwMS whose cultured PBMCs underwent ex vivo MBP stimulation, IL-17 production declined with age in women (β=-0.27, p=0.04) but not men (β=-0.1, p=0.73). MBP-driven IL-17 response partially mediated the association between older age and lower ARR (24.7% in women, 15.3% in men). In exploratory analyses, older pwMS (≥50 years) had marginally lower (IL-4, MCP-2, MCP-3, PDGF-AA, PDGF-AB/BB) and higher (Fractalkine, MDC) concentrations of several cytokines than younger pwMS (<50 years), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR.

Diminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation.

Misshapen/NIKs-related kinase (MINK) 1 belongs to the mammalian germinal center kinase (GCK) family. It contains the N-terminal, conserved kinase domain, a coiled-coil region, a proline-rich region, and a GCK, C-terminal domain with the Citron-NIK-Homology (CNH) domain. The kinase is an essential component of cellular signaling pathways, which include Wnt signaling, JNK signaling, pathways engaging Ras proteins, the Hippo pathway, and STRIPAK complexes. It thus contributes to regulating the cell cycle, apoptosis, cytoskeleton organization, cell migration, embryogenesis, or tissue homeostasis. MINK1 plays an important role in immunological responses, inhibiting Th17 and Th1 cell differentiation and regulating NLRP3 inflammasome function. It may be considered a link between ROS and the immunological system, and a potential antiviral target for human enteroviruses. The kinase has been implicated in the pathogenesis of sepsis, rheumatoid arthritis, asthma, SLE, and more. It is also involved in tumorigenesis and drug resistance in cancer. Silencing MINK1 reduces cancer cell migration, suggesting potential for new therapeutic approaches. Targeting MINK1 could be a promising treatment strategy for patients insensitive to current chemotherapies, and could improve their prognosis. Moreover, MINK1 plays an important role in the nervous system and the cardiovascular system development and function. The modulation of MINK1 activity could influence the course of neurodegenerative diseases, including Alzheimer's disease. Further exploration of the activity of the kinase could also help in gaining more insight into factors involved in thrombosis or congenital heart disease. This review aims to summarize the current knowledge on MINK1, highlight its therapeutic and prognostic potential, and encourage more studies in this area.