Type Cytokines Research Articles

COVID-19 PBMCs are doubly harmful, through LDN-mediated lung epithelial damage and monocytic impaired responsiveness to live Pseudomonas aeruginosa exposure.

Although many studies have underscored the importance of T cells, phenotypically and functionally, fewer have studied the functions of myeloid cells in COVID disease. In particular, the potential role of myeloid cells such as monocytes and low-density neutrophils (LDNs) in innate responses and particular in the defense against secondary bacterial infections has been much less documented. Here, we compared, in a longitudinal study, healthy subjects, idiopathic fibrosis patients, COVID patients who were either hospitalized/moderate (M-) or admitted to ICU (COV-ICU) and patients in ICU hospitalized for other reasons (non-COV-ICU). We show that COVID patients have an increased proportion of low-density neutrophils (LDNs), which produce high levels of proteases (particularly, NE, MMP-8 and MMP-9) (unlike non-COV-ICU patients), which are partly responsible for causing type II alveolar cell damage in co-culture experiments. In addition, we showed that M- and ICU-COVID monocytes had reduced responsiveness towards further live Pseudomonas aeruginosa (PAO1 strain) infection, an important pathogen colonizing COVID patients in ICU, as assessed by an impaired secretion of myeloid cytokines (IL-1, TNF, IL-8,…). By contrast, lymphoid cytokines (in particular type 2/type 3) levels remained high, both basally and post PAO1 infection, as reflected by the unimpaired capacity of T cells to proliferate, when stimulated with anti-CD3/CD28 beads. Overall, our results demonstrate that COVID circulatory T cells have a biased type 2/3 phenotype, unconducive to proper anti-viral responses and that myeloid cells have a dual deleterious phenotype, through their LDN-mediated damaging effect on alveolar cells and their impaired responsiveness (monocyte-mediated) towards bacterial pathogens such as P. aeruginosa.

CXCL13/CXCR5 axis mediates IgM+ B cell migration through AKT and STAT3 signaling pathways in Nile tilapia (Oreochromis niloticus)

Chemokine C-X-C motif ligand 13 (CXCL13), originally identified as a B-lymphocyte chemokine, exerts a crucial role in the chemotaxis of B cells through its receptor CXCR5. Although the presence of CXCL13/CXCR5 had been reported in various teleost fish species, its impact on IgM+ B cell still remains unknown. In this study, we investigated the role of chemokine CXCL13 and its receptor CXCR5 in the chemotaxis of IgM+ B cells in Nile tilapia (Oreochromis niloticus). We identified and characterized two isotypes of OnCXCL13 (OnCXCL13a and OnCXCL13b) and CXCR5 (OnCXCR5) in Nile tilapia. The OnCXCL13 is characterized with a typical small cytokine CXC domain and four cysteine, in which the first two cysteines separated by a random amino acid residue, and OnCXCR5 is characterized by seven α-helical transmembrane domains. Both OnCXCL13 and OnCXCR5 were found to be expressed in various tissues and lymphocytes, with the highest expression in the spleen (SPL). Their expression in IgM+ B cells was significantly higher than that in IgM− lymphocytes. Following Streptococcus agalactiae infection, the expressions of OnCXCL13a and OnCXCL13b were up-regulated in peripheral blood (PBL), SPL and head kidney (HK), while OnCXCR5 was significantly up-regulated in SPL and HK. We also found that the recombinant OnCXCL13 proteins had strong chemotactic activity on IgM+ B cells, which could be inhibited by blocking OnCXCR5 with anti-OnCXCR5 antibody. Mechanistically, incubation with OnCXCL13 resulted in the up-regulation of AKT and STAT3 phosphorylation in IgM+ B cells, which could be attenuated by specific inhibitors of AKT and STAT3. Inhibition of AKT and STAT3 also weakened the chemotaxis of OnCXCL13 on IgM+ B cells. Our results suggest that the CXCL13/CXCR5 axis participates in the immune response of tilapia and mediates the chemotaxis of IgM+ B cells, providing insights into the potential role of this axis in bacterial infection and teleost B cell migration.

The Possible Roles of IL-4/IL-13 in the Development of Eosinophil-Predominant Severe Asthma.

Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play roles in the development of bronchial asthma. Among these cytokines, IL-4 is involved in T-cell differentiation, B-cell activation, B-cell differentiation into plasma cells, and the production of immunoglobulin E. Although IL-13 has similar effects to IL-4, IL-13 mainly affects structural cells, such as epithelial cells, smooth muscle cells, and fibroblasts. IL-13 induces the differentiation of goblet cells that produce mucus and induces the airway remodeling, including smooth muscle hypertrophy. IL-4 and IL-13 do not directly activate the effector functions of eosinophils; however, they can induce eosinophilic airway inflammation by upregulating the expression of vascular cell adhesion molecule-1 (for adhesion) and CC chemokine receptor 3 ligands (for migration). Dupilumab, a human anti-IL-4 receptor α monoclonal antibody that inhibits IL-4 and IL-13 signaling, decreases asthma exacerbations and mucus plugs and increases lung function in moderate to severe asthma. In addition, dupilumab is effective for chronic rhinosinusitis with nasal polyps and for atopic dermatitis, and IL-4/IL-13 blocking is expected to suppress allergen sensitization, including transcutaneous sensitization and atopic march.

Immunologic Profiling of Immune-Related Cutaneous Adverse Events with Checkpoint Inhibitors Reveals Polarized Actionable Pathways.

Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood. Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.

Myeloid A20 is critical for alternative macrophage polarization and type-2 immune-mediated helminth resistance.

Protective immunity against intestinal helminths requires induction of robust type-2 immunity orchestrated by various cellular and soluble effectors which promote goblet cell hyperplasia, mucus production, epithelial proliferation, and smooth muscle contractions to expel worms and re-establish immune homeostasis. Conversely, defects in type-2 immunity result in ineffective helminth clearance, persistent infection, and inflammation. Macrophages are highly plastic cells that acquire an alternatively activated state during helminth infection, but they were previously shown to be dispensable for resistance to Trichuris muris infection. We use the in vivo mouse model A20myel-KO, characterized by the deletion of the potent anti-inflammatory factor A20 (TNFAIP3) specifically in the myeloid cells, the excessive type-1 cytokine production, and the development of spontaneous arthritis. We infect A20myel-KO mice with the gastrointestinal helminth Trichuris muris and we analyzed the innate and adaptive responses. We performed RNA sequencing on sorted myeloid cells to investigate the role of A20 on macrophage polarization and type-2 immunity. Moreover, we assess in A20myel-KO mice the pharmacological inhibition of type-1 cytokine pathways on helminth clearance and the infection with Salmonella typhimurium. We show that proper macrophage polarization is essential for helminth clearance, and we identify A20 as an essential myeloid factor for the induction of type-2 immune responses against Trichuris muris. A20myel-KO mice are characterized by persistent Trichuris muris infection and intestinal inflammation. Myeloid A20 deficiency induces strong classical macrophage polarization which impedes anti-helminth type-2 immune activation; however, it promotes detrimental Th1/Th17 responses. Antibody-mediated neutralization of the type-1 cytokines IFN-γ, IL-18, and IL-12 prevents myeloid-orchestrated Th1 polarization and re-establishes type-2-mediated protective immunity against T. muris in A20myel-KO mice. In contrast, the strong Th1-biased immunity in A20myel-KO mice offers protection against Salmonella typhimurium infection. We hereby identify A20 as a critical myeloid factor for correct macrophage polarization and appropriate adaptive mucosal immunity in response to helminth and enteric bacterial infection.

Evodiamine Alleviates 2,4-Dinitro-1-Chloro-Benzene-Induced Atopic Dermatitis-like Symptoms in BALB/c Mice.

Evodiamine is an alkaloid found in Evodia fruits, a traditional Chinese medicine. Preclinical studies have demonstrated its anti-inflammatory and neuroprotective properties. The 2,4-dinitro-1-chloro-benzene (DNCB) was used to test the effects of evodiamine on a chemically induced atopic dermatitis-like model in BALB/c mice. Evodiamine significantly lowered serum immunoglobulin E levels, which increased as an immune response to the long-term application of DNCB. Several atopic dermatitis-like skin symptoms induced by DNCB, including skin thickening and mast cell accumulation, were suppressed by evodiamine therapy. DNCB induced higher levels of pro-inflammatory cytokines in type 2 helper T (Th2) cells (IL-4 and IL-13), Th1 cells (IFN-γ and IL-12A), Th17 cells (IL-17A), Th22 cells (IL-22), and chemokines (IL-6 and IL-8). These increases were suppressed in the lymph nodes and skin following evodiamine treatment. The results of our study indicate that evodiamine suppresses atopic dermatitis-like responses in mice and may therefore be useful in treating these conditions.

The Prostaglandin D2 Receptor CRTH2 Contributes to Airway Hyperresponsiveness during Airway Inflammation Induced by Sensitization without an Adjuvant in Mice

Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells.

Tezepelumab: patient selection and place in therapy in severe asthma.

Asthma is a disease characterised by heterogeneous and multifaceted airway inflammation. Despite the availability of effective treatments, a substantial percentage of patients with the type 2 (T2)-high, but mainly the T2-low, phenotype complain of persistent symptoms, airflow limitation, and poor response to treatments. Currently available biologicals target T2 cytokines, but no monoclonal antibodies or other specific therapeutic options are available for non-T2 asthma. However, targeted therapy against alarmins is radically changing this perspective. The development of alarmin-targeted therapies, of which tezepelumab (TZP) is the first example, may offer broad action on inflammatory pathways as well as an enhanced therapeutic effect on epithelial dysfunction. In this regard, TZP demonstrated positive results not only in patients with severe T2 asthma but also those with non-allergic, non-eosinophilic disease. Therefore, it is necessary to identify clinical features of patients who can benefit from an upstream targeted therapy such as anti-thymic stromal lymphopoietin. The aims of this narrative review are to understand the role of alarmins in asthma pathogenesis and epithelial dysfunction, examine the rationale underlying the indication of TZP treatment in severe asthma, summarise the results of clinical studies, and recognise the specific characteristics of patients potentially eligible for TZP treatment.

Targeting Common Inflammatory Mediators in Experimental Severe Asthma and Acute Lung Injury.

Neutrophils, known to be mobilized and activated in high amounts through Il-17 stimulation, are a key factor for clinical manifestation and imbalance of redox systems favoring a dominant oxidative state in both severe asthma and acute lung injury (f). The aim of this study was to evaluate in mice, the effect of Secukinumab (SECU) in a model of ovalbumin-induced asthma exacerbated with LPS administration to induce ALI, compared to dexamethasone (DEXA), already known for its benefit in both asthma and ALI. Results on cytokine levels for specific Th1, Th2 and Th17 revealed an interplay of immune responses. For Th1 effector cytokines in BALF, DEXA treatment increased TNF-α levels, but TNF-α was not modified by SECU; DEXA and SECU significantly decreased IFN-γ and IL-6 levels. For typical Th2 cytokines, DEXA significantly increased Il-4, Il-5 and Il-13 levels, while SECU significantly inhibited Il-5 levels. Both SECU and DEXA significantly decreased Il-17 levels. Cytokine level changes in lung tissue homogenate were partly similar to BALF cytokines. Conclusion: in addition to DEXA, SECU possesses the ability to modulate inflammatory cytokine release and to decrease Th17 responses in ALI overlapped on exacerbated asthma in mice.

Eosinophils Are an Endogenous Source of Interleukin-4 during Filarial Infections and Contribute to the Development of an Optimal T Helper 2 Response

Plain Language SummaryFilarial nematodes can cause severe diseases like onchocerciasis and lymphatic filariasis, posing a significant public health challenge in tropical regions, putting over a billion people at risk. The WHO categorizes these infections as neglected tropical diseases and aims to eliminate onchocerciasis transmission and lymphatic filariasis as a public health issue by 2030. Filarial nematodes modulate the immune system of their host, and the induction of protective immune responses still requires a better understanding. Eosinophils have been identified as a key immune cell type in the well-established murine model for filarial infection, Litomosoides sigmodontis. However, their precise roles and interactions with other components of the type 2 immune response remain unclear. Our study reveals that eosinophils play a crucial role as a primary source of interleukin-4, the central cytokine in type 2 immunity. By using dblGATA mice, we found that the absence of eosinophils resulted in a reduced T helper 2 response but did not impact the alternative activation of macrophages or antibody production. In summary, our research uncovers an underappreciated function of eosinophils and their significant influence on type 2 immune responses.

Mechanism of Chinese sturgeon IFN-γ inhibition on Mycobacterium marinum (Acipenser sinensis)

IFN-γ plays a crucial role in both innate and adaptive immune responses and is a typical Th1 cytokine that promotes Th1 response and activates macrophages. When macrophages were incubated with IFN-γ, their phagocytosis ratio against Mycobacterium marinum increased significantly, as observed under fluorescence microscopy. The macrophages engulfed a large number of M. marinum. The proliferative ability of macrophages treated with IFN-γ was significantly weaker on the 4th and 7th day after phagocytosis and subsequent re-infection with marine chlamydia (P < 0.001). This suggests that IFN-γ enhances the phagocytosis and killing ability of macrophages against M. marinum. IFN-γ protein also significantly increased the production of reactive oxygen species (H2O2) and nitric oxide (NO) by macrophages. Additionally, the expression levels of toll-like receptor 2 (tlr2) and caspase 8 (casp8) were significantly higher in macrophages after IFN-γ incubation compared to direct infection after 12 h of M. marinum stimulation. Apoptosis was also observed to a higher degree in IFN-γ incubated macrophage. Moreover, mRNA expression of major histocompatibility complex (MHC) molecules produced by macrophages after IFN-γ incubation was significantly higher than direct infection. This indicates that IFN-γ enhances antigen presentation by upregulating MHC expression. It also upregulates tlr2 and casp8 expression through the TLR2 signaling pathway to induce apoptosis in macrophages. The pro-inflammatory cytokine showed an initial increase followed by a decline, suggesting that IFN-γ enhances the immune response of macrophages against M. marinum infection. On the other hand, the anti-inflammatory cytokine showed a delayed increase, significantly reducing the expression of pro-inflammatory cytokines. The expression of both cytokines balanced each other and together regulated the inflammatory reaction against M. marinum infection.

Role of IL-4 and IL-13 in Cutaneous T Cell Lymphoma.

The interleukins IL-4 and IL-13 are increasingly recognized contributors to the pathogenesis of cutaneous T cell lymphomas (CTCLs), and their role in disease-associated pruritus is accepted. The prevailing Th2 profile in advanced CTCL underscores the significance of understanding IL-4/IL-13 expression dynamics from the early stages of disease, as a shift from Th1 to Th2 may explain CTCL progression. Targeted agents blocking key cytokines of type 2 immunity are established therapeutics in atopic disorders and have a promising therapeutic potential in CTCL, given their involvement in cutaneous symptoms and their contribution to the pathogenesis of disease. IL-4, IL-13, and IL-31 are implicated in pruritus, offering therapeutic targets with dupilumab, tralokinumab, lebrikizumab, and nemolizumab. This review analyzes current knowledge on the IL-4/IL-13 axis in mycosis fungoides and Sezary syndrome, the most common types of CTCL, examining existing literature on the pathogenetic implications with a focus on investigational treatments. Clinical trials and case reports are required to shed light on novel uses of medications in various diseases, and ongoing research into the role of IL-4/IL-13 axis blockers in CTCL therapy might not only improve the management of disease-related pruritus but also provide in-depth insights on the pathophysiologic mechanisms of CTCL.

Schistosoma mansoni co-infection modulates Chagas disease development but does not impair the effect of benznidazole-based chemotherapy

The adequate management of parasite co-infections represents a challenge that has not yet been overcome, especially considering that the pathological outcomes and responses to treatment are poorly understood. Thus, this study aimed to evaluate the impact of Schistosoma mansoni infection on the efficacy of benznidazole (BZN)-based chemotherapy in Trypanosoma cruzi co-infected mice. BALB/c mice were maintained uninfected or co-infected with S. mansoni and T. cruzi, and were untreated or treated with BZN. Body weight, mortality, parasitemia, cardiac parasitism, circulating cytokines (Th1/Th2/Th17); as well as heart, liver and intestine microstructure were analyzed. The parasitemia peak was five times higher and myocarditis was more severe in co-infected than T. cruzi-infected mice. After reaching peak, parasitemia was effectively controlled in co-infected animals. BZN successfully controlled parasitemia in both co-infected and T. cruzi-infected mice and improved body mass, cardiac parasitism, myocarditis and survival in co-infected mice. Co-infection dampened the typical cytokine response to either parasite, and BZN reduced anti-inflammatory cytokines in co-infected mice. Despite BZN normalizing splenomegaly and liver cellular infiltration, it exacerbated hepatomegaly in co-infected mice. Co-infection or BZN exerted no effect on hepatic granulomas, but increased pulmonary and intestinal granulomas. Marked granulomatous inflammation was identified in the small intestine of all schistosomiasis groups. Taken together, our findings indicate that BZN retains its therapeutic efficacy against T. cruzi infection even in the presence of S. mansoni co-infection, but with organ-specific repercussions, especially in the liver.

An Atlas of the Hidradenitis Suppurativa Transcriptome.

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin. Both genetic and environmental factors contribute to the risk of developing HS, but the pathogenesis of this disease is currently not fully understood. The aim of this study was to further current understanding of the molecular background of HS with the use of global transcriptome analyses. Transcriptome profiling of perilesional and lesional skin of five patients with HS and six healthy control patients was performed by next-generation sequencing. Groups of differentially expressed genes characteristic of the skin of patients with HS were shortlisted by bioinformatic analysis. RNA sequencing followed by bioinformatic profiling revealed profound enrichment of inflammatory-related processes in both lesional and perilesional skin of patients with HS. There were, however, distinct differences in the gene expression profiles between the lesional and perilesional skin, with 1488 genes differentially expressed. Genes encoding typical proinflammatory cytokines were profoundly enriched within HS lesions. In contrast, those encoding mediators of extracellular matrix organization were highly expressed mostly in the perilesional area. Our study provides novel insights into the mechanisms underlying the pathogenesis of HS, and the results also have potential clinical implications in both diagnosis and therapeutics.

Airways Type-2 Related Disorders: Multiorgan, Systemic or Syndemic Disease?

Chronic rhinosinusitis (CRS) has recently undergone a significant paradigm shift, moving from a phenotypical classification towards an "endotype-based" definition that places more emphasis on clinical and therapeutic aspects. Similar to other airway diseases, like asthma, most cases of CRS in developed countries exhibit a dysregulated type-2 immune response and related cytokines. Consequently, the traditional distinction between upper and lower airways has been replaced by a "united airway" perspective. Additionally, type-2 related disorders extend beyond respiratory boundaries, encompassing conditions beyond the airways, such as atopic dermatitis. This necessitates a multidisciplinary approach. Moreover, consideration of possible systemic implications is crucial, particularly in relation to sleep-related breathing diseases like Obstructive Sleep Apnoea Syndrome (OSAS) and the alteration of systemic inflammatory mediators such as nitric oxide. The trends in epidemiological, economic, and social burden are progressively increasing worldwide, indicating syndemic characteristics. In light of these insights, this narrative review aims to present the latest evidence on respiratory type-2 related disorders, with a specific focus on CRS while promoting a comprehensive perspective on the "united airways". It also introduces a novel concept: viewing these conditions as a multiorgan, systemic, and syndemic disease.

Voluntary exercise improves pulmonary inflammation through NF-κB and Nrf2 in type 2 diabetic male rats.

This study aimed to evaluate the effects of voluntary exercise as an anti-inflammatory intervention on the pulmonary levels of inflammatory cytokines in type 2 diabetic male rats. Twenty-eight male Wistar rats were divided into four groups (n=7), including control (Col), diabetic (Dia), voluntary exercise (Exe), and diabetic with voluntary exercise (Dia+Exe). Diabetes was induced by a high-fat diet (4 weeks) and intraperitoneal injection of streptozotocin (35 mg/kg), and animals did training on the running wheel for 10 weeks as voluntary exercise. Finally, the rats were euthanized and the lung tissues were sampled for the evaluation of the levels of pulmonary interleukin (IL)-10, IL-11, and TNF-α using ELISA, and the protein levels of Nrf-2 and NF-κB using western blotting and tissue histopathological analysis. Diabetes reduced the IL-10, IL-11, and Nrf2 levels (P<0.001 to P<0.01) and increased the levels of TNF-α and NF-κB compared to the Col group (P<0.001). Lung tissue levels of IL-10, IL-11, and Nrf2 in the Dia+Exe group enhanced compared to the Dia group (P<0.001 to P<0.05), however; the TNF-α and NF-κB levels decreased (P<0.001). The level of pulmonary Nrf2 in the Dia+Exe group was lower than that of the Exe group while the NF-κB level increased (P<0.001). Moreover, diabetes caused histopathological changes in lung tissue which improved with exercise in the Dia+Exe group. These findings showed that voluntary exercise could improve diabetes-induced pulmonary complications by ameliorating inflammatory conditions.

����� ����ղ����� �����: ����������, �ֲ��� ���������� ��������, ��² ����������� �����ò��ί ����ϲ� ��ֲ��Ҳ�

According to general estimates, from 3�5 % and up to 10 % of patients with asthma have a severe course of the disease, which often continues to remain uncontrolled, despite the maximum use of inhaled corticosteroids and additional controller drugs. Severe asthma creates a large physical, mental, emotional, social and economic burden for patients and is often associated with multimorbidity. The heterogeneity of asthma drives research aimed at defining asthma phenotypes that ultimately reflect different underlying disease mechanisms, including pathogenetic processes and response to environmental factors. The clinical phenotypes of asthma are closely related to the underlying inflammatory processes in this disease and therefore can be divided into 2 main inflammatory phenotypes determined by the dominant immunological pathways that determine the pathology of bronchial asthma: eosinophilic and non-eosinophilic. Phenotyping patients is important for the differential diagnosis of asthma, risk assessment, treatment selection, and monitoring response to treatment. Accurate identification of the phenotype is particularly important for the selection of a biological drug for the treatment of severe asthma and for predicting the response to treatment with it. But these phenotypes are not fixed and can change over time in response to new environmental triggers (viral infections, inhaled allergens, smoking, air pollution). The main cytokines in the T2 type of inflammation in the airways, which is characteristic of severe asthma, are IL-4, IL-5 and IL- 13, IL-17, but an equally significant role in this process is also played by alarmins (inflammation mediators produced, in particular, cells of the bronchial epithelium), which include IL-33, IL-25 and thymic stromal lymphopoietin (TSLP). Clinical features of asthma associated with TSLP include: 1) degree of severity; 2) risk and frequency of exacerbations; 3) the degree of lung function decline; 4) decrease in the patient's response to glucocorticosteroids; 5) decrease in immune response and susceptibility to acute respiratory viral infections; 6) potential remodulation of the respiratory tract; 7) bronchial hyperreactivity and mucus blockage. Therefore, the role of TSLP in the pathogenesis of severe asthma is very significant, so its therapeutic effect (anti-TSLP therapy using tezepelumab) can be considered a new promising direction of biological therapy for patients with bronchial asthma, especially in its severe form. Key words: bronchial asthma, severe form, type 2 inflammation, biomarkers of inflammation, thymic stromal lymphopoietin, biological therapy, tezepelumab.

Effects of metformin on arterial elasticity and pro-inflammatory markers in black diabetes patients.

Pro-inflammatory markers are linked with the development and progression of type 2 diabetes mellitus and arterial stiffening. Pulse Wave Velocity (PWV) and Augmentation Index (Aix) are non-invasive standard markers of arterial elasticity and predictors of cardiovascular mortality and morbidity. To investigate the effects of metformin alone and in combination with glimepiride on arterial elasticity, pro-inflammatory cytokines in black type 2 diabetes mellitus patients. Participants were enrolled from Sefako Makgatho Health Sciences University community, Gauteng, South Africa. PWV and Aix were measured using the AtCor SphygmoCor® system (AtCor Medical, Inc., Sydney, Australia). Cytokines levels were measured using Multiplexing with Bio-Plex Pro™ human inflammation panel I assay. Treatment naïve type 2 diabetes participants were divided into two groups: metformin (M) (n = 10) and metformin glimepiride (MS) (n = 14). The study participants were followed up at 4 and 8 months after treatment initiation. In the M and MS, IL-1β increased significantly at four months (58.19 ± 0.03 pg/ml, 58.35 ± 0.30 pg/ml) when compared to baseline (33.05 ± 18.56 pg/ml, 34.79 ± 18.77 pg/ml) then decreased significantly at eight months (29.25 ± 11.64 pg/ml, 32.54 ± 14.26 pg/ml) when compared to four months (58.19 ± 0.03 pg/ml, 58.35 ± 0.3 pg/ml) (p < 0.05). There were no significant changes in PWV, Aix, IL-1ra, IL-2, IL-6, IL-8, TNF-α and hs-CRP levels at both treatment intervals. Metformin alone or in combination with glimepiride did not improve arterial elasticity and did not reduce pro-inflammatory cytokines levels in T2DM black South African patients. The context-based knowledge generated by the current study is expected to enhance the continuum of care for T2DM patients.

Hyaluronic acid-functionalized nanoparticles for ulcerative colitis-targeted therapy: a comparative study of oral administration and intravenous injection.

Targeted delivery of anti-inflammatory drugs to macrophages has attracted great attention for selectively alleviating the symptoms of ulcerative colitis (UC), while minimizing adverse effects. Herein, we aimed to compare the in vivo pharmacokinetics and therapeutic outcomes of macrophage-targeted nanoparticles (NPs) via oral administration and intravenous injection. Polymeric NPs were employed to load an anti-inflammatory drug (curcumin, CUR), followed by surface functionalization with hyaluronic acid (HA). The resulting HA-CUR-NPs had an average diameter of 281 nm and a negatively charged surface. These NPs showed excellent biocompatibility and a significantly higher cell internalization efficiency in RAW 264.7 macrophages compared with their counterparts (carboxymethyl cellulose-functionalized CUR-encapsulated NPs, CUL-CUR-NPs). Moreover, HA-CUR-NPs exhibited a dramatically stronger capacity to inhibit the mRNA expression levels of the typical pro-inflammatory cytokines from lipopolysaccharide-stimulated macrophages compared with CUL-CUR-NPs. In vivo experiments revealed that HA-CUR-NPs after i.v. injection could improve the pharmacokinetics of CUR, and that it showed much better UC therapeutic outcomes compared with the oral administration way. Collectively, in comparison with HA-CUR-NPs (oral), HA-CUR-NPs (i.v.) possess a higher CUR delivery efficiency to the colitis mucosa, which can be developed as an efficient platform for UC treatment.

Mustard seed major allergen Sin a1 activates intestinal epithelial cells and also dendritic cells that drive type 2 immune responses.

Mustard seeds belong to the food category of mandatory labelling due to the severe reactions they can trigger in allergic patients. However, the mechanisms underlying allergic sensitization to mustard seeds are poorly understood. The aim of this work is to study type 2 immune activation induced by the mustard seed major allergen Sin a1 via the intestinal mucosa, employing an in vitro model mimicking allergen exposure via the intestinal epithelial cells (IECs). Sin a1 was isolated from the total protein extract and exposed to IEC, monocyte derived dendritic cells (DCs) or IEC/DC co-cultures. A system of consecutive co-cultures was employed to study the generic capacity of Sin a1 to induce type 2 activation leading to sensitization: IEC/DC, DC/T-cell, T/B-cell and stem cell derived mast cells (MCs) derived from healthy donors. Immune profiles were determined by ELISA and flow cytometry. Sin a1 activated IEC and induced type-2 cytokine secretion in IEC/DC co-culture or DC alone (IL-15, IL-25 and TSLP), and primed DC induced type 2 T-cell skewing. IgG secretion in the T-cell/B-cell phase was enhanced in the presence of Sin a1 in the first stages of the co-culture. Anti-IgE did not induce degranulation but promoted IL-13 and IL-4 release by MC primed with the supernatant from B-cells co-cultured with Sin a1-IEC/DC or -DC primed T-cells. Sin a1 enhanced the release of type-2 inflammatory mediators by epithelial and dendritic cells; the latter instructed generic type-2 responses in T-cells that resulted in B-cell activation, and finally MC activation upon anti-IgE exposure. This indicates that via activation of IEC and/or DC, mustard seed allergen Sin a1 is capable of driving type 2 immunity which may lead to allergic sensitization.