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Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches.

Heart failure is often the consequence of insufficient cardiac regeneration. Neonatal mice retain a certain capability of myocardial regeneration until postnatal day (P)7, although the underlying transcriptional mechanisms remain largely unknown. We demonstrate here that cardiac abundance of the transcription factor GATA4 was high at P1, but became strongly reduced at P7 in parallel with loss of regenerative capacity. Reconstitution of cardiac GATA4 levels by adenoviral gene transfer markedly improved cardiac regeneration after cryoinjury at P7. In contrast, the myocardial scar was larger in cardiomyocyte‐specific Gata4 knockout (CM‐G4‐KO) mice after cryoinjury at P0, indicative of impaired regeneration, which was accompanied by reduced cardiomyocyte proliferation and reduced myocardial angiogenesis in CM‐G4‐KO mice. Cardiomyocyte proliferation was also diminished in cardiac explants from CM‐G4‐KO mice and in isolated cardiomyocytes with reduced GATA4 expression. Mechanistically, decreased GATA4 levels caused the downregulation of several pro‐regenerative genes (among them interleukin‐13, Il13 ) in the myocardium. Interestingly, systemic administration of IL‐13 rescued defective heart regeneration in CM‐G4‐KO mice and could be evaluated as therapeutic strategy in the future. Synopsis Why heart regeneration in mice is no longer possible after the age of 7 days remains unknown. Here, the robust downregulation of cardiac GATA4 levels occurring around the same time is shown to be at least in part responsible for this phenomenon. Cardiac GATA4 expression is strongly downregulated (by about 70–80%) between postnatal day 1 (P1) and P7 in parallel with the loss of regenerative capacity of the heart. Reconstitution of cardiac GATA4 levels by adenoviral gene transfer after P7 enhances cardiac regeneration after cryoinjury by promoting cardiomyocyte proliferation and angiogenesis. Cardiomyocyte‐specific ablation of GATA4 decreases neonatal heart regeneration. GATA4 promotes regeneration by inducing regenerative genes in the heart, such as IL‐13, cyclin A2, or IGF‐2R. Graphical Abstract Why heart regeneration in mice is no longer possible after the age of 7 days remains unknown. Here, the robust downregulation of cardiac GATA4 levels occurring around the same time is shown to be at least in part responsible for this phenomenon.

Background Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease, primarily affecting the elderly. The role of interleukin‐13 (IL‐13) in BP pathogenesis remains unclear, particularly regarding its potential as a therapeutic target. Objectives To evaluate differences in serum IL‐13 levels between idiopathic and drug‐induced BP patients and healthy controls, and to investigate correlations between IL‐13 levels, disease severity, mucosal involvement, and prognosis. Methods This retrospective cohort study included 42 BP patients diagnosed between 2008 and 2023 at a dermatology referral center, along with 12 healthy controls and four pemphigus vulgaris patients. Serum IL‐13 levels were measured using ELISA. The primary outcomes were IL‐13 levels and their association with disease etiology, eosinophil counts, mucosal involvement, and the need for adjuvant therapy. Results Serum IL‐13 levels were lower in BP patients (n = 42, mean 62.46 pg/mL ± 16.53) compared to healthy controls (n = 12, mean 87.83 pg/mL ±8.87, p < 0.0001) and pemphigus patients (n = 4, mean 87.6 pg/mL ± 5.16, p = 0.013). Idiopathic BP patients exhibited higher IL‐13 levels than Dipeptidyl peptidase‐4 (DPP4) ‐induced BP patients (67.01 pg/mL ± 14.3 vs. 57.36 pg/mL ± 21, p = 0.0104). No significant correlation was found between IL‐13 levels and mucosal involvement (p = 0.338), eosinophil counts (Pearson correlation coefficient = 0.18, p = 0.253), the need for adjuvant therapy (p = 0.32), or prognosis (p = 0.45). Higher eosinophil levels correlated with the need for adjuvant therapy (p = 0.027). Conclusions Serum IL‐13 levels are lower in BP patients compared to healthy controls, and in DPP4‐induced BP compared to idiopathic BP, suggesting a complex role of IL‐13 in BP pathogenesis. IL‐13 levels did not correlate with disease severity or prognosis, indicating that IL‐13 may not be a reliable marker for BP severity or outcome. Further research is needed to clarify IL‐13's role in BP and to guide therapeutic strategies.

Oral submucous fibrosis (OSF) is a chronic progressive fibrosis disease that affects in oral mucosal tissues. Interleukin (IL)‐13 has been implicated in the development of fibrosis in multiple organs. Indeed, it contributes to diseases such as pulmonary fibrosis, liver cirrhosis among others. Currently, its expression in OSF and the specific mechanisms are not well understood. The aim of this study was to investigate the role of IL‐13 in OSF and further explore whether IL‐13 regulates—polarization of M2‐macrophages in OSF. Initially, in the tissues of patients with OSF, we observed a high expression of M2‐macrophages and IL‐13 protein. Additionally, we found a correlation between the expression of IL‐13 and the stage of OSF. Arecoline inhibited the proliferation of fibroblasts (FBs) and promoted IL‐13 production in vitro. Furthermore, our observations revealed that M2‐macrophages increased upon co‐culturing M0‐macrophages with supernatants containing the IL‐13 cytokine. In conclusion, our study demonstrated that arecoline stimulates FBs leading to increased secretion of IL‐13, which in turn IL‐13 leads to polarization of M2‐macrophages and promotes the occurrence of OSF. This suggests that IL‐13 may be a potential therapeutic target of OSF.

Background Lebrikizumab is a monoclonal antibody that modulates activity of interleukin‐13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard‐of‐care treatment. Methods Adolescents (aged 12–17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%–90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks. Results Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg (n = 116) reduced the exacerbation rate at 52 weeks versus placebo (n = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28–0.83]; 51% rate reduction). Lebrikizumab 37.5 mg (n = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35–1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/μl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21–0.89]; 37.5 mg: 0.42 [95% CI 0.19–0.93]). Treatment‐emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred. Conclusion Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results. Clinical trial registration NCT01875003 (www.ClinicalTrials.gov).

The role of eosinophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) remains ambiguous and likely differs from its role in asthma. The molecular processes underlying the differences between eosinophils from asthma and COPD have not been sufficiently studied. The objective of this study was to compare the transcriptomic profiles of blood eosinophils in COPD and asthma. Eosinophils were isolated from peripheral blood drawn from stable mild‐to‐moderate COPD and asthma patients. RNA was isolated from eosinophils and sequenced using an NGSelect RNA. The prepared libraries were sequenced on an Illumina platform. The study group included five patients with asthma and four patients with COPD. The RNA‐Seq data analysis identified 26 differentially expressed genes between COPD and asthma (according to adjusted p‐value). In total, 6 genes were upregulated (e.g. CCL3L1, CCL4L2, GPR82) and 20 were downregulated (e.g. JUN, IFITM3, DUSP1, GNG7) in peripheral eosinophils of COPD patients compared to asthma. The genes associated with signalling of IL‐4 and IL‐13 pathways were downregulated in COPD eosinophils compared to asthma. In conclusion, blood eosinophils from COPD and asthma patients present different transcriptomic profiles suggesting their different function in pathobiology of both obstructive airway diseases. These differences might indicate the direction of the search of targeted therapy in COPD.

SLC26A9 is an epithelial anion transporter with a poorly defined function in airways. It is assumed to contribute to airway chloride secretion and airway surface hydration. However, immunohistochemistry showing precise localization of SLC26A9 in airways is missing. Some studies report localization near tight junctions, which is difficult to reconcile with a chloride secretory function of SLC26A9. We therefore performed immunocytochemistry of SLC26A9 in sections of human and porcine lungs. Obvious apical localization of SLC26A9 was detected in human and porcine superficial airway epithelia, whereas submucosal glands did not express SLC26A9. The anion transporter was located exclusively in ciliated epithelial cells. Highly differentiated BCi-NS1 human airway epithelial cells grown on permeable supports also expressed SLC26A9 in the apical membrane of ciliated epithelial cells. BCi-NS1 cells expressed the major Cl− transporting proteins CFTR, TMEM16A and SLC26A9 in about equal proportions and produced short-circuit currents activated by increases in intracellular cAMP or Ca2+. Both CFTR and SLC26A9 contribute to basal chloride currents in non-stimulated BCi-NS1 airway epithelia, with CFTR being the dominating Cl− conductance. In wtCFTR-expressing CFBE human airway epithelial cells, SLC26A9 was partially located in the plasma membrane, whereas CFBE cells expressing F508del-CFTR showed exclusive cytosolic localization of SLC26A9. Membrane localization of SLC26A9 and basal chloride currents were augmented by interleukin 13 in wild-type CFTR-expressing cells, but not in cells expressing the most common disease-causing mutant F508del-CFTR. The data suggest an upregulation of SLC26A9-dependent chloride secretion in asthma, but not in the presence of F508del-CFTR.

IL‐33 is an IL‐1‐related cytokine that can act as an alarmin when released from necrotic cells. Once released, it can target various immune cells including mast cells, innate lymphoid cells and T cells to elicit a Th2‐like immune response. We show here that bone marrow‐derived mast cells produce IL‐13, IL‐6, TNF, GM‐CSF, CCL3 and CCL4 in response to IL‐33 stimulation. Inhibition of the p38 MAPK, or inhibition or knockout of its downstream kinases MK2 and MK3, blocked the production of these cytokines in response to IL‐33. The mechanism downstream of MK2/3 was cytokine specific; however, MK2 and MK3 were able to regulate TNF and GM‐CSF mRNA stability. Previous studies in macrophages have shown that MK2 regulates mRNA stability via phosphorylation of the RNA‐binding protein TTP (Zfp36). The regulation of cytokine production in mast cells was, however, independent of TTP. MK2/3 were able to phosphorylate the TTP‐related protein Brf1 (Zfp36 l1) in IL‐33‐stimulated mast cells, suggesting a mechanism by which MK2/3 might control mRNA stability in these cells. In line with its ability to regulate in vitro IL‐33‐stimulated cytokine production, double knockout of MK2 and 3 in mice prevented neutrophil recruitment following intraperitoneal injection of IL‐33. Knockout or inhibition of MK2 and MK3 blocks IL‐33‐induced cytokine and chemokine production in mast cells. In line with this, MK2/3 knockouts fail to recruit neutrophils in vivo in response to IL‐33.

Background Intensive care unit‐acquired weakness (ICU‐AW) is a syndrome characterized by a long‐term muscle weakness often observed in sepsis‐surviving patients during the chronic phase. Although ICU‐AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death‐1 (PD‐1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU‐AW remains to be elucidated. Here, we study how PD‐1 deficiency affects sepsis‐induced skeletal muscle dysfunction in a preclinical sepsis model. Methods Chronic sepsis model was developed by treating wild‐type (WT) and PD‐1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL‐13) and PD‐1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow‐twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT‐qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL‐13 followed by gene expression measurements. Results WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long‐term muscle weakness (P < 0.0001), whereas PD‐1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow‐twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD‐1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow‐twitch mRNAs, which was restored by IL‐13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL‐13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL‐13‐producing ILC2s in skeletal muscle were examined and found to increase in PD‐1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2‐derived IL‐13 was increased by PD‐1 KO septic mice and thought to protect the muscles from experimental ICU‐AW. Conclusions Long‐term muscle weakness in experimental ICU‐AW was ameliorated in PD‐1 KO mice. ILC2‐derived IL‐13 production in skeletal muscles was increased in PD‐1 KO mice, thereby suggesting that IL‐13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD‐1 blockade in preserving muscle strength during sepsis through an increase in ILC2‐derived IL‐13 and may be an attractive therapeutic target for sepsis‐induced ICU‐AW.

Objective To investigate the effects of secukinumab treatment for psoriasis on different functional cytokines and inflammatory mediators in patients’ serum Methods Enzyme‐linked immunosorbent assay was used to detect interleukin (IL)‐1β and IL‐1RA associated with intrinsic immunity; IL‐6, IL‐18, and growth regulated oncogene alpha (GROα) associated with neutrophils; IL‐12, tumour necrosis factor (TNF)‐α, and interferon (IFN)‐γ associated with Th1; IL‐23, IL‐17A, and IL‐22 associated with Th17; Thymus activation regulated chemokine (TARC), IL‐13, and defensin beta 2 (DEFB2) associated with Th2; Vascular endothelial growth factor (VEGF)‐A and IL‐10 associated with angiogenesis; and IFN‐γ associated with sepsis in the peripheral blood of 12 patients with common psoriasis treated with secukinumab and 15 healthy controls. IL‐23, IL‐17A, IL‐22 associated with Th17; TARC, IL‐13, DEFB2 associated with Th2; VEGF‐A, IL‐10 associated with angiogenesis and procalcitonin (PCT) associated with sepsis. The differences in expression of the above cytokines before and after treatment and the correlation with psoriasis disease severity［Psoriasis Area Severity Index(PASI) score］, age, and disease duration were analyzed. Results The mean PASI score of the enrolled patients with moderate to severe psoriasis was 21.6 ± 11.0 before treatment and decreased to below 1 after treatment. Serum IL‐6; IL‐18, GROα, IFN‐γ, TNF‐α, VEGF‐A, and IL‐17A were significantly higher than normal. And IL‐17A and IFN‐γ were positively correlated with disease duration and age, and IL‐18 was positively correlated with PASI score. The expression levels of IL‐6, GROα, VEGF‐A, IFN‐γ, TNF‐α, IL‐17A and IL‐23 were significantly lower after secukinumab treatment compared with those before treatment, but the expression levels of IFN‐γ, VEGF‐A, TARC, IL‐13, and DEFB2 were still significantly higher than those of normal subjects after treatment Conclusions secukinumab clears skin lesions by antagonizing IL‐17A and simultaneously decreasing the expression levels of IL‐6, GRO α, VEGF‐A, IFN‐γ, TNF‐α, IL‐17A, and IL‐23.