Bacterial Lysate-Based Bifunctional mRNA Nanoformulation for Efficient Colon Cancer Immunogene Therapy.

mRNA-based nonviral gene therapy has played an important role in cancer therapy, however, the limited delivery efficiency and therapeutic capacity still require further exploration and enhancement. Immunogene therapy provides a strategy for cancer treatment. Bacteria are tiny single-celled living organisms, many of which can be found in and on the human body and are beneficial to humans. Lactobacillus reuteri is a bacterial member of the gut flora, and recent research has shown that it can reduce intestinal inflammation by stimulating an immunomodulatory response. L. reuteri lysate represents an ideal resource for constructing advanced mRNA delivery systems with immune stimulation potential. Here, we prepared a bifunctional mRNA delivery system DMP-Lac (DOTAP-mPEG-PCL-L. reuteri lysate), which successfully codelivered L. reuteri lysate and IL-23A mRNA, exhibited a high mRNA delivery efficiency of 75.56% ± 0.85%, and strongly promoted the maturation and activation of the immune system in vivo. Both the CT26 abdominal metastasis model and the lung metastasis model also exhibited a good therapeutic effect, and the tumor inhibition rate of DMP-Lac/IL-23A group reached 97.92%. Protein chip technology verified that DMP acted as an immune adjuvant, demonstrating that the L. reuteri lysate could regulate the related immune cells, while IL-23 mRNA caused changes in downstream factors, thus producing the corresponding tumor treatment effect. The DMP-Lac/IL-23A complex exhibited strong anticancer immunotherapeutic effects. Our results demonstrated that this bifunctional mRNA formulation served as a tumor-specific nanomedicine, providing an advanced strategy for colon cancer immunogene therapy.

Eczematous reactions in patients with plaque psoriasis receiving biological therapy: an observational study.

OBJECTIVE: The use of biologic agents, mainly tumor necrosis factor (TNF)-α and interleukin (IL)-17A inhibitors, was associated with cutaneous side effects, but the factors associated with eczematous reactions occurring during biologic treatments are not completely known. PATIENTS AND METHODS: An observational, retrospective, multicentre Italian study evaluated the clinical features and the management of eczematous eruptions in 54 patients with chronic plaque psoriasis who developed eczema after treatment with biological agents (anti-IL-17 or 23). RESULTS: Many of these patients had personal and family history of atopy. Eczematous reactions developed between a few days and 3 years after initiation of the biologic drug. The highest proportion of cases associated with eczematous reactions during biologic treatments was seen in patients on anti-IL-17 agents, including brodalumab. We observed that eczema rapidly remitted without relapse in all patients who switched to anti-IL-23 agents. Among our cases, fast responders to psoriasis therapy seem to have more persistent eczematous reactions. CONCLUSIONS: Patients with psoriasis and a history of atopic dermatitis should be treated with an IL-23 inhibitor due to its efficacy in psoriasis and the rarely reported eczematous reaction.

Distinctive CD39+CD9+ lung interstitial macrophages suppress IL-23/Th17-mediated neutrophilic asthma by inhibiting NETosis.

The IL-23-Th17 axis is responsible for neutrophilic inflammation in various inflammatory diseases. Here, we discover a potential pathway to inhibit neutrophilic asthma. In our neutrophil-dominant asthma (NDA) model, single-cell RNA-seq analysis identifies a subpopulation of CD39+CD9+ interstitial macrophages (IMs) suppressed by IL-23 in NDA conditions but increased by an IL-23 inhibitor αIL-23p19. Adoptively transferred CD39+CD9+ IMs suppress neutrophil extracellular trap formation (NETosis), a representative phenotype of NDA, and also Th17 cell activation and neutrophilic inflammation. CD39+CD9+ IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP near neutrophils that contribute to NETosis in a CD39-dependent manner. Transcriptomic data from asthmatic patients finally show decreased CD39+CD9+ IMs in severe asthma than mild/moderate asthma. Our results suggest that CD39+CD9+ IMs function as a potent negative regulator of neutrophilic inflammation by suppressing NETosis in the IL-23-Th17 axis and can thus serve as a potential therapeutic target for IL-23-Th17-mediated neutrophilic asthma.

IL-23 inhibition for chronic inflammatory disease.

Biological monoclonal antibody drugs inhibit overactive cytokine signalling that drives chronic inflammatory disease in different organ systems. In the last 10 years, interleukin (IL)-23 inhibitors have attained an important position in the treatment of psoriatic skin and joint disease as well as inflammatory bowel diseases. Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response that extends dosing intervals up to 3 months. Pooled clinical trial data show objective disease improvement for more than 70% of patients with psoriasis and up to 50% of patients with inflammatory bowel disease. The first antibody inhibitor for IL-23A targeted a p40 subunit shared with IL-12. Subsequently, even greater improvement was established for inhibitors of the p19 protein unique to IL-23A. IL-23 p19 inhibitors elicit clinical response in both bio-naive and bio-exposed patients and show superiority to tumour necrosis factor α inhibitors in plaque psoriasis. Reported differences in efficacy between p19 inhibitors suggest that individual drug action might be modulated by antibody affinity. Although long-term safety data are accumulating, rates of serious adverse events and infections for interleukin (IL)-23 inhibitors are similar to the rates for placebo across approved indications.

In vitro silencing of RIP2 in naive CD4+ T cells from lupus-prone mice promotes pathogenic Th17 cell differentiation.

OBJECTIVE: This work aims to investigate whether RIP2 silencing in naive CD4+ T cells from lupus-prone mice impacts Th17 cell activity or differentiation in vitro. METHODS: Naive CD4+ T cells isolation from MRL/lpr mice's spleens. Three RNA interference target sequences of RIP2 were packaged with lentivirus and transfected into naive CD4+ T cells. The shRIP2 with the highest interference efficiency was selected and transfected into naive CD4+ T cells. Naive CD4+ T cells were cultured under conventional (TGF-ß1 and IL-6) and pathogenic (IL-6, IL-23, IL-1ß) differentiation environments, respectively. Then, RT-qPCR, Western blot or Flow Cytometry were used for measuring the amounts of RIP2 and IL-17 and the differentiation of Th17 cells in two settings. RESULTS: Under the conventional Th17 (cTh17) cell differentiation environment (TGF-ß1 and IL-6), RIP2 deficiency is linked to decreased IL-17A levels (1.00 ± 0.03 vs 0.80 ± 0.03) and attenuated cTh17 cell (2.46 ± 0.08 vs 0.78 ± 0.03) differentiation (all, P < 0.05). Under the pathogenic Th17 (pTh17) cell environment (IL-1ß, IL-23, IL-6), RIP2 deficiency is linked to elevated IL-17A levels (1.03 ± 0.05 vs 1.63 ± 0.07) and enhanced pTh17 cell (3.69 ± 0.19 vs 5.49 ± 0.10) differentiation (all, P < 0.05). CONCLUSION: Our data suggest that RIP2 inhibition induces preferential differentiation of naive CD4+ T cells to pathogenic Th17 cells, while being able to upregulate IL-17A levels in the context of pTh17 cell differentiation. Our study opens up new research areas to reveal the underlying mechanisms and potential therapeutic targets for the prevention and treatment of SLE patients. Key Points • Silencing of RIP2 in naive CD4+ T cells from lupus-prone mice promotes pathogenic Th17 (pTh17) cell differentiation and IL-17A production under pTh17 cell (IL-1ß, IL-23, and IL-6) conditions. • RIP2 deficiency in naive CD4+ T cells reduces conventional Th17 (cTh17) cell differentiation and IL-17A production under cTh17 cell (TGF-ß1 and IL-6) conditions. • RIP2-deficient naive CD4+ T cells preferentially differentiate towards pTh17 cells rather than cTh17 cells in vitro. • Inhibition of RIP2 may be involved in the development of SLE via effects on Th17/IL-17.

The immunologic role of IL-23 in psoriatic arthritis: a potential therapeutic target.

INTRODUCTION: Psoriatic arthritis (PsA) is a debilitating chronic condition characterized by inflammation of the joints, bones, enthesis, and skin. The pivotal role of interleukin-23 (IL-23) in the pathogenesis of PsA has become increasingly evident. This proinflammatory cytokine is markedly elevated in patients with PsA, suggesting its potential as a therapeutic target. Consequently, IL-23 inhibitors have emerged as promising first-line biologic treatments for PsA. AREAS COVERED: This review delves into the immunopathogenic mechanisms of IL-23 at the cellular and molecular levels in PsA. Furthermore, it provides the recent efficacy and safety profiles of IL-23 inhibitors. We conducted a literature search in PubMed for the following terms: 'IL-23 and psoriatic arthritis,' 'Ustekinumab,' 'Guselkumab,' 'Risankizumab,' and 'Tildrakizumab.' In addition, we retrieved clinical trials involving IL-23 inhibitors registered in ClinicalTrials.gov, EudraCT, and ICTRP. EXPERT OPINION: Despite the promising outcomes observed with IL-23 inhibitors, several challenges persist. The long-term effects of these agents require further investigation through prospective studies, and their limited accessibility worldwide necessitates urgent attention. Additionally, ongoing research is warranted to explore other potential drug targets within the IL-23/IL-23 R axis. The development of reliable biomarkers could greatly enhance early detection, tailored management strategies, and personalized treatment approaches for patients with PsA.

The mode of action of IL-23 in experimental inflammatory arthritic pain and disease.

OBJECTIVES: We have previously reported using gene-deficient mice that the interleukin (IL)-23p19 subunit is required for the development of innate immune-driven arthritic pain and disease. We aimed to explore here, using a number of in vivo approaches, how the IL-23p19 subunit can mechanistically control arthritic pain and disease in a T- and B- lymphocyte-independent manner. METHODS: We used the zymosan-induced arthritis (ZIA) model in wild-type and Il23p19-/- mice, by a radiation chimera approach, and by single cell RNAseq and qPCR analyses, to identify the IL23p19-expressing and IL-23-responding cell type(s) in the inflamed joints. This model was also utilized to investigate the efficacy of IL-23p19 subunit blockade with a neutralizing monoclonal antibody (mAb). A novel IL-23-driven arthritis model was established, allowing the identification of putative downstream mediators of IL-23 in the control of pain and disease. Pain and arthritis were assessed by relative static weight distribution and histology, respectively. RESULTS: We present evidence that (i) IL-23p19+ non-bone marrow-derived macrophages are required for the development of ZIA pain and disease, (ii) prophylactic and therapeutic blockade of the IL-23p19 subunit ameliorate ZIA pain and disease and (iii) systemically administered IL-23 can induce arthritic pain and disease in a manner dependent on TNF, GM-CSF, CCL17 and cyclooxygenase activity, but independently of lymphocytes, CGRP, NGF and substance P. CONCLUSIONS: The data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.

BACKGROUND: Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. METHODS: The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. RESULTS: Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response. CONCLUSIONS: Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.

Bone marrow mesenchymal stromal cells attenuate smoke inhalation injury by regulating the M1/M2-Th17/Treg immune homeostasis axis.

Smoke inhalation injury (SII) is the leading cause of death in fire burn patients. The inflammatory response induced by smoke inhalation is a significant factor in the development of acute lung injury or acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) can alleviate various inflammatory diseases by regulating the polarization of macrophages from the M1 to the M2 phenotype. Moreover, MSCs can facilitate the inflammatory response by regulating Th17/Treg homeostasis. However, little is known about the associations among MSCs, M1/M2 macrophages and Th17/Treg homeostasis. Therefore, the purpose of this study was to evaluate whether MSCs affect subsequent Th17/Treg differentiation and immune homeostasis by regulating M1/M2 polarization in SII. Our results showed that bone marrow mesenchymal stem cells (BMSCs) ameliorated lung inflammatory injury and fibrosis after SII by affecting the polarization of alveolar macrophages (AMs) from the M1 to the M2 phenotype. Moreover, BMSCs maintain Th17/Treg immune homeostasis by increasing the proportion of Treg cells and decreasing the proportion of Th17 cells. In vitro, we further demonstrated that BMSCs promoted the polarization of AMs from the M1 to the M2 phenotype and decreased IL-23 levels. Reduced IL-23 decreased Th17 differentiation and promoted Th17/Treg balance. Therefore, BMSCs ameliorate the inflammatory response and lung damage after SII through regulating M1/M2 polarization and subsequent Th17/Treg immune homeostasis, which are linked to alveolar macrophage-derived IL-23. These findings provide novel insight into how BMSCs regulate the M1/M2-Th17/Treg immune homeostasis axis and provide new therapeutic targets for more effective control of the inflammatory response after SII.

A new Anticalin protein for IL-23 inhibits non-type 2 allergen-driven mouse lung inflammation and airway hyperresponsiveness.

Severe asthma is a syndromic label assigned to patients based on clinical parameters, yet there are diverse underlying molecular endotypes in severe asthma pathobiology. Immunophenotyping of asthma biospecimens commonly includes a mixture of granulocytes and lymphocytes. Recently, a subset of patients with severe asthma was defined as non-type 2 with neutrophil-enriched inflammation associated with increased Th17 CD4+ T cells and IL-17 levels. Here, we used an allergen-driven mouse model of increased IL-17 and mixed granulocyte lung inflammation to determine the impact of upstream regulation by an Anticalin protein that specifically binds IL-23. Airway administration of the IL-23-binding Anticalin protein (AcIL-23) decreased lung neutrophils, eosinophils, macrophages, lymphocytes, IL-17+ CD4 T cells, mucous cell metaplasia, and methacholine-induced airway hyperresponsiveness. Selective targeting of IL-23 with a monoclonal antibody (IL-23p19; αIL-23) also decreased macrophages, IL-17+ CD4 T cells, and airway hyperresponsiveness. In contrast, a monoclonal antibody against IL-17A (αIL-17A) had no significant effect on airway hyperresponsiveness but did decrease lung neutrophils, macrophages, and IL-17+ CD4 T cells. Targeting the IL-23 pathway did not significantly change IL-5+ or IL-13+ CD4 T cells. Together, these data indicate that airway AcIL-23 mirrored the activity of systemic anti-IL-23 antibody to decrease airway hyperresponsiveness in addition to mixed granulocytic inflammation and that these protective actions were broader than blocking IL-17A or IL-5 alone, which selectively decreased airway neutrophils and eosinophils, respectively.NEW & NOTEWORTHY This is the first report of an Anticalin protein engineered to neutralize IL-23 (AcIL-23). Airway administration of AcIL-23 in mice regulated allergen-driven airway inflammation, mucous cell metaplasia, and methacholine-induced airway hyperresponsiveness. In mixed granulocytic allergic lung inflammation, immune regulation of IL-23 was broader than neutralization of either IL-17 or IL-5.

Successful management of pre-existing psoriatic arthritis through targeting the IL-23/IL-17 axis in cancer patients receiving immune checkpoint inhibitor therapy: a case series.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with cancer. However, these therapies are associated with adverse events including de novo immune-related adverse events or flare of pre-exiting autoimmune disorders. Up to 80% of patients with cancer and pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) experience PsO/PsA flare after initiating ICIs. Targeting the interleukin (IL)-17/IL-23 axis is a mainstream of the PsO/PsA treatment. However, whether this treatment can effectively control PsO/PsA with ICI exposure while preserving anti-tumour efficacy remains unknown. CASE REPORTS: We report three patients with PsA and cancer, who received ICIs for their cancer treatment. All patients were male. Two patients had clear cell renal cell carcinoma, and one had melanoma. Two patients received anti-PD-1 antibody monotherapy, while one patient received combined anti-CTLA-4 and PD-1 antibody therapy. One patient had been receiving anti-IL-17A antibody (secukinumab), while the other two patients started anti-IL-17A antibody (ixekizumab) and anti-IL-23 antibody (guselkumab) after their PsA flared up during ICI treatment. Of note, with the anti-IL-17A or anti-IL-23 antibody treatment, their PsA remained in remission, and they well tolerated the ICI therapy. Importantly, all three patients showed persistent tumour responses to ICI therapy, including two complete remissions and one stable disease, respectively. CONCLUSIONS: These three cases suggest that targeting the IL-17/23 axis may be an effective and safe approach for patients with cancer and pre-existing PsA being considered for ICI therapy.

Dendritic Cells Promote the Differentiation of ILCs into NCR-ILC3s in the Lungs of Mice Exposed to Cigarette Smoke.

The involvement of Group 3 innate lymphoid cells (ILC3s) and dendritic cells (DCs) in chronic lung inflammation has been increasingly regarded as the key to understand the inflammatory mechanisms of smoke-related chronic obstructive pulmonary disease (COPD). However, the mechanism underlying the engagement of both remains unclear. Our study aimed to explore NCR-ILC3 differentiation in the lungs of mice exposed to cigarette smoke (CS) and to further investigate whether DCs activated by CS exposure contribute to the differentiation of ILCs into NCR-ILC3s. The study involved both in vivo and in vitro experiments. In the former, the frequencies of lung NCR-ILC3s and NKp46-IL-17A+ ILCs and the expression of DCs, CD40, CD86, IL-23, and IL-1ß quantified by flow cytometry were compared between CS-exposed mice and air-exposed mice. In the latter, NKp46-IL-17A+ ILC frequencies quantified by flow cytometry were compared after two cocultures, one involving lung CD45+Lin-CD127+ ILCs sorted from air-exposed mice and DCs sifted by CD11c magnetic beads from CS-exposed mice and another including identical CD45+Lin-CD127+ ILCs and DCs from air-exposed mice. The results indicated significant increases in the frequencies of NCR-ILC3s and NKp46-IL-17A+ ILCs; in the expression of DCs, CD40, CD86, IL-23, and IL-1ß in CS-exposed mice; and in the frequency of NKp46-IL-17A+ ILCs after the coculture with DCs from CS-exposed mice. In conclusion, CS exposure increases the frequency of lung ILCs and NCR-ILC3s. CS-induced DC activation enhances the differentiation of ILCs into NCR-ILC3s, which likely acts as a mediating step in the involvement of NCR-ILC3s in chronic lung inflammation.

Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease.

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

IL-23 Priming Enhances the Neuroprotective Effects of MSC-Derived Exosomes in Treating Retinal Degeneration.

Purpose: Neuroinflammation is a characteristic feature of neurodegenerative diseases. Mesenchymal stem cell-derived exosomes (MSC-exo) have shown neuroprotective effects through immunoregulation, but the therapeutic efficacy remains unsatisfactory. This study aims to enhance the neuroprotective capacity of MSC-exo through IL-23 priming for treating retinal degeneration in mice. Methods: MSC were primed with IL-23 stimulation in vitro, and subsequently, exosomes (MSC-exo and IL-23-MSC-exo) were isolated and characterized. Two retinal degenerative disease models (NaIO3-induced mice and rd10 mice) received intravitreal injections of these exosomes. The efficacy of exosomes was assessed by examining retinal structural and functional recovery. Furthermore, exosomal microRNA (miRNA) sequencing was conducted, and the effects of exosomes on the M1 and M2 microglial phenotype shift were evaluated. Results: IL-23-primed MSC-derived exosomes (IL-23-MSC-exo) exhibited enhanced capability in protecting photoreceptor cells and retinal pigment epithelium (RPE) cells against degenerative damage and fostering the restoration of retinal neural function in both NaIO3-induced retinal degeneration mice and rd10 mice when compared with MSC-exo. The exosomal miRNA suppression via Drosha knockdown in IL-23-primed MSC would abolish the neuroprotective role of IL-23-MSC-exo, highlighting the miRNA-dependent mechanism. Bioinformatic analysis, along with further in vivo biological studies, revealed that IL-23 priming induced a set of anti-inflammatory miRNAs in MSC-exo, prompting the transition of M1 to M2 microglial polarization. Conclusions: IL-23 priming presents as a potential avenue for amplifying the immunomodulatory and neuroprotective effects of MSC-exo in treating retinal degeneration.

Sequencing of Targeted Therapy in Psoriasis: Does it Matter?

With the continued development of biologics for the treatment of psoriasis, some patients have achieved optimal control, but a recommended biologic sequence if a biologic fails to initially improve the skin, termed primary nonresponse, or loses efficacy after initial improvement, termed secondary nonresponse, is still lacking. Primary and secondary nonresponse can occur with any class of biologics, and the type of nonresponse can drive the choice of whether to switch within a biologic class or to a different biologic class. The choice of biologic can also be challenging when managing psoriasis and concomitant psoriatic arthritis, as treatment differs on the basis of the severity of both diseases and further classification of axial and peripheral joint involvement. When choosing a biologic, each patient's comorbidities and preferences are also taken into account to provide the optimal therapy. With this lack of an established biologic sequence after biologic failure, the objective of our review is to define a therapy sequence for the tumor necrosis factor (TNF), interleukin-17 (IL-17), and interleukin-23 (IL-23) inhibitor classes in the treatment of psoriasis and psoriatic arthritis. Our proposed biologic sequence was derived through an analysis of the efficacy of each biologic class, primary and secondary nonresponse rates from clinical trials, and clinical experience with expert opinion.

Interleukin 23 versus interleukin 12/23 inhibitors on preventing incidental psoriatic arthritis in patients with psoriasis? A real-world comparison from the TriNetX Global Collaborative Network.

BACKGROUND: Managing psoriasis (PsO) and its comorbidities, particularly psoriatic arthritis, often involves using interleukin (IL)-23 and IL-12/23 inhibitors. However, the comparative risk of these treatments still needs to be explored. OBJECTIVE: This study evaluates the risk of developing psoriatic arthritis in patients treated with IL-23 inhibitors compared to IL-12/23 inhibitors. METHODS: This retrospective cohort study utilized data from the TriNetX, including adult patients diagnosed with PsO. Patients with IL-23 or IL-12/23 inhibitors treatment were included and propensity score matched. The primary outcome was the incidence of psoriatic arthritis (PsA), analyzed using a Cox regression hazard model and Kaplan-Meier estimates. RESULTS: The study included matched cohorts of patients treated with IL-23 inhibitors (n = 2273) and IL-12/23 inhibitors (n = 2995). Cox regression analysis revealed no significant difference in the cumulative incidence of PsA between the IL-23i and IL-12/23i cohorts (P = .812). Kaplan-Meier estimates confirmed similar cumulative incidences of arthropathic PsO in both cohorts over the study period. LIMITATION: Long-term follow-up studies are required to understand more of the effects of these interleukin inhibitors. CONCLUSION: No significant difference but a numerically lower risk of psoriatic arthritis in PsO patients treated with IL-23 inhibitors than with IL-12/23 inhibitors was found, underscoring their comparable efficacy in PsO management and follow-up.

Illuminating the impact of γδ T cells in man and mice in spondylarthritides.

Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity.

JNJ-77242113, a highly potent, selective peptide targeting the IL-23 receptor, provides robust IL-23 pathway inhibition upon oral dosing in rats and humans.

The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (KD: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC50: 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23-induced interferon (IFN)γ production in NK cells, and in blood from healthy donors and psoriasis patients (IC50: 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses ≥ 0.3 mg/kg/day. Pharmacologic activity beyond the gastrointestinal tract was also demonstrated. In blood from rats receiving oral JNJ-77242113, dose-dependent inhibition of ex vivo IL-23-stimulated IL-17A production was observed. In an IL-23-induced rat skin inflammation model, JNJ-77242113 inhibited IL-23-induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23-stimulated IFNγ production in whole blood. Thus, JNJ-77242113 provided selective, systemic IL-23 pathway inhibition in preclinical models which translated to pharmacodynamic activity in healthy human volunteers, supporting the potential for JNJ-77242113 as a selective oral therapy for IL-23-driven immune-mediated diseases.

The relationship between TNF-α, IL-1, IL-12, IL-17, IL-23, IL-36 expression and treatment response in psoriasis histopathologically and immunohistochemically.

AIM: There is no marker that can predict whether there is resistance to treatment in patients with psoriasis. In this study, we investigated the relationship between the staining rates of TNF-α, IL-1, IL-12, IL-17, IL-23, and IL-36 markers immunohistochemically from cutaneous biopsy and the treatment success. METHODS: The patients who were followed up in the dermatology clinic with the diagnosis of plaque-type psoriasis vulgaris and received biological treatment and previously had cutaneous biopsy were included in the study. The cutaneous biopsies of the cases that met the conditions were re-sectioned and subjected to immunohistochemical examination for TNF-α, IL-1, IL-12, IL-17, IL-23, and IL-36. RESULTS: Comparing the staining scores with psoriasis area severity index (PASI); A statistically significant positive correlation was found between PASI and TNF-α staining score (p = 0.034). A statistically significant positive correlation was found between PASI and IL-17 staining score (p = 0.004). When the staining scores and PASI response rates of psoriasis treatment were evaluated in terms of correlation; there was a positive correlation between TNF-α, IL-17, and IL-23 immunohistochemical staining rates and PASI response rates. CONCLUSIONS: In line with the data obtained from our study, we think that making immunohistochemical scoring before the biological treatment decision in psoriasis patients will be beneficial in treatment selection. In this respect, our study may open a new era in the selection of biological treatments for psoriasis.

Momordin Ic ameliorates psoriasis skin damage in mice via the IL-23/IL-17 axis.

Psoriasis, a chronic and easily recurring inflammatory skin disease, causes a great economic burden to the patient's family because the etiology and mechanism are still unclear and the treatment cycle is long. In this study, the function and related mechanisms of Momordin Ic in psoriasis were investigated. The IMQ-induced mouse psoriasis model was constructed. The protective effects of different doses of Momordin Ic on psoriasis skin damage in mice were detected by PASI score, HE staining and Ki-67 staining. A psoriasis-like keratinocyte model was established at the cellular level using M5 (IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α) triggered HaCaT. The effects of Momordin Ic upon HaCaT cell biological behavior were examined using MTT and CCK-8 assays. In terms of mechanism, the expression level of each inflammatory factor was assessed using IHC staining and/or ELISA, qRT-PCR, the expression of oxidative stress-related indicators was detected biochemically, and western blot was performed to detect the levels of key proteins of the Wnt signaling and VEGF. As the results shown,  at the in vivo level, Momordin Ic significantly alleviated skin damage, reduced PASI score and inhibited hyperproliferation of keratinized cells in psoriasis mice. At the cellular level, Momordin Ic also significantly reversed M5-induced hyperproliferation of HaCaT keratinocytes. In terms of mechanism, Momordin Ic significantly inhibited the IL-23/IL-17 axis, dramatically elevated the levels of intracellular antioxidants including SOD, GSH-Px, and CAT, and significantly down-regulated the levels of the indicator of oxidative damage, malondialdehyde (MDA). In addition, Momordin Ic also significantly inhibited the level of ß-catenin, a pivotal protein of the Wnt signaling, C-Myc, a target gene of the Wnt signaling, and VEGF, a critical protein of angiogenesis. In conclusion, Momordin Ic can be involved in the skin-protective effects of psoriasis by multiple mechanisms, including inhibition of the Wnt signaling pathway and the IL-23/IL-17 axis, and suppression of oxidative damageand VEGF expression. Momordin Ic has been proven to be an underlying therapeutic drug for the treatment of psoriasis.