Long-term immune response accompanies clinical outcomes in severe asthmatics treated with anti-IL-5/IL-5R biologics

This work was supported by ISCIII - Instituto de Salud Carlos III, FIS (Fondo de Investigación Sanitaria - Spanish Health Research Fund) grants PI21/00896 and FI19/00067; Ciber de Enfermedades Respiratorias (CIBERES); SEAIC grants 22A07; BASEAS STUDY (Basophils in EosinophilicAsthma) Study Code ESR-20-20764 AstraZeneca International; Comunidad de Madrid grant PEJ2021-AI_BMD-22320 and FEDER funds (Fondo Europeo de Desarrollo Regiona

Nuevo papel de los eosinófilos en la respuesta inmune

Tesis doctoral inédita leida en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 30-6-199

MicroRNAs as potential regulators of immune response networks in asthma and chronic obstructive pulmonary disease

Chronic respiratory diseases (CRDs) are an important factor of morbidity and mortality, accounting for approximately 6% of total deaths worldwide. The main CRDs are asthma and chronic obstructive pulmonary disease (COPD). These complex diseases have different triggers including allergens, pollutants, tobacco smoke, and other risk factors. It is important to highlight that although CRDs are incurable, various forms of treatment improve shortness of breath and quality of life. The search for tools that can ensure accurate diagnosis and treatment is crucial. MicroRNAs (miRNAs) are small non-coding RNAs and have been described as promising diagnostic and therapeutic biomarkers for CRDs. They are implicated in multiple processes of asthma and COPD, regulating pathways associated with inflammation, thereby showing that miRNAs are critical regulators of the immune response. Indeed, miRNAs have been found to be deregulated in several biofluids (sputum, bronchoalveolar lavage, and serum) and in both structural lung and immune cells of patients in comparison to healthy subjects, showing their potential role as biomarkers. Also, miRNAs play a part in the development or termination of histopathological changes and comorbidities, revealing the complexity of miRNA regulation and opening up new treatment possibilities. Finally, miRNAs have been proposed as prognostic tools in response to both conventional and biologic treatments for asthma or COPD, and miRNA-based treatment has emerged as a potential approach for clinical intervention in these respiratory diseases; however, this field is still in development. The present review applies a systems biology approach to the understanding of miRNA regulatory networks in asthma and COPD, summarizing their roles in pathophysiology, diagnosis, and treatmentThis manuscript was supported by Fondo de Investigación Sanitaria – FIS and FEDER (Fondo Europeo de Desarrollo Regional) [PI15/00803, PI18/00044 and FI16/00036], CIBERES, Merck Health Foundation funds and RTC-2017-6501-1 (Ministerio de Ciencia, Innovación y Universidades

Enhanced anti-inflammatory effects of mesenchymal stromal cells mediated by the transient ectopic expression of CXCR4 and IL10

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliationsBackground Mesenchymal stromal cells (MSCs) constitute one of the cell types most frequently used in cell therapy. Although several studies have shown the efficacy of these cells to modulate inflammation in different animal models, the results obtained in human clinical trials have been more modest. Here, we aimed at improving the therapeutic properties of MSCs by inducing a transient expression of two molecules that could enhance two different properties of these cells. With the purpose of improving MSC migration towards inflamed sites, we induced a transient expression of the C-X-C chemokine receptor type 4 (CXCR4). Additionally, to augment the anti-inflammatory properties of MSCs, a transient expression of the anti-inflammatory cytokine, interleukin 10 (IL10), was also induced. Methods Human adipose tissue-derived MSCs were transfected with messenger RNAs carrying the codon-optimized versions of CXCR4 and/or IL10. mRNA-transfected MSCs were then studied, first to evaluate whether the characteristic phenotype of MSCs was modified. Additionally, in vitro and also in vivo studies in an LPS-induced inflamed pad model were conducted to evaluate the impact associated to the transient expression of CXCR4 and/or IL10 in MSCs. Results Transfection of MSCs with CXCR4 and/or IL10 mRNAs induced a transient expression of these molecules without modifying the characteristic phenotype of MSCs. In vitro studies then revealed that the ectopic expression of CXCR4 significantly enhanced the migration of MSCs towards SDF-1, while an increased immunosuppression was associated with the ectopic expression of IL10. Finally, in vivo experiments showed that the co-expression of CXCR4 and IL10 increased the homing of MSCs into inflamed pads and induced an enhanced anti-inflammatory effect, compared to wild-type MSCs. Conclusions Our results demonstrate that the transient co-expression of CXCR4 and IL10 enhances the therapeutic potential of MSCs in a local inflammation mouse model, suggesting that these mRNA-modified cells may constitute a new step in the development of more efficient cell therapies for the treatment of inflammatory diseasesThis work was supported by the following public grants: Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III Ministerio de Ciencia, Innovación y Universidades and Fondo Europeo de Desarrollo Regional (FEDER) ((RETICS-RD16/0011/0011, PIE15/00048, PI18-01379), and Dirección General de Investigación de la Comunidad de Madrid (AvanCell-CM; Ref S2017/BMD-3692