Cannabinoid WIN55212-2 impairs peanut-allergic sensitization and promotes the generation of allergen-specific regulatory T cells

Background: Cannabinoids are lipid-derived mediators with anti-inflammatory prop-erties in different diseases. WIN55212-2, a non-selective synthetic cannabinoid, re-duces immediate anaphylactic reactions in a mouse model of peanut allergy, but its capacity to prevent peanut-allergic sensitization and the underlying mechanisms re-mains largely unknown. Objective: To investigate the capacity of WIN55212-2 to immunomodulate peanut- stimulated human dendritic cells (DCs) and peanut-allergic sensitization in mice. Methods: Surface markers and cytokines were quantified by flow cytometry, ELISA and qPCR in human monocyte-derived DCs (hmoDCs) and T-cell cocultures after stimulation with peanut alone or in the presence of WIN55212-2. Mice were epicuta-neously sensitized with peanut alone or peanut/WIN55212-2. After peanut challenge, drop in body temperature, haematocrit, clinical symptoms, peanut-specific antibodies in serum and FOXP3+ regulatory (Treg) cells in spleen and lymph nodes were quanti-fied. Splenocytes were stimulated in vitro with peanut to analyse allergen-specific T- cell responses. Results: WIN55212-2 reduced peanut-induced hmoDC activation and promoted the generation of CD4+CD127−CD25+FOXP3+ Treg cells, while reducing the induction of IL- 5- producing T cells. In vivo, WIN55212-2 impaired the peanut-induced migration of DCs to lymph nodes and their maturation. WIN55212-2 significantly reduced the induction of peanut-specific IgE and IgG1 antibodies in serum during epicutaneous peanut sensitization, reduced the clinical symptoms score upon peanut challenge and promoted the generation of allergen-specific FOXP3+ Treg cells. Conclusions: The synthetic cannabinoid WIN55212-2 interferes with peanut sensi-tization and promotes tolerogenic responses, which might well pave the way for the development of novel prophylactic and therapeutic strategies for peanut allergy

The cannabinoid WIN55212-2 restores rhinovirus-induced epithelial barrier disruption

Carta al Editor. Received: 19 September 2020 | Revised: 20 November 2020 | Accepted: 5 December 2020Sección Deptal. de Química Orgánica (Óptica y Optometría)Fac. de Óptica y OptometríaTRUEMinisterio de Economía y Competitividad de España (MINECO)Swiss National Science FoundationChristine Kühne‐Center for Allergy Research and Education (CK‐CARE) (Suiza)Universidad Complutense de Madrid (España)inpres

Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming

The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases

IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity

Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Emulsifying properties of whey protein concentrate and caseinomacropeptide of cow, ewe and goat

The emulsifying activity index was shown to be significantly higher in the case of the whey protein concentrate (WPC) compared to caseinomacropeptides (CMP) (185 and 36 m2.g-1, respectively). The emulsifying activity index showed a dependent behaviour on pH and protein concentration for WMP and three CMPs. The emulsifying stability index of WMP changed significantly with pH and ionic strength. For CMPs from the 3 different species, the emulsifying stability did not show a significant variability with respect to pH but showed a dependence on ionic strength. The CMPs had a more stable emulsifying activity index with respect to pH than WMP, suggesting the possible utilisation of CMP as an emulsifier in foods which undergo large pH variations during processing (i.e. fermented dairy products).Peer Reviewe

Comparison of foaming capacity of caseinmacropeptide from different species with whey protein concentrate

Foaming properties were analysed for whey protein concentrate (WPC) and compared with those of caseinmacropeptides (CMPs) isolated from cow, ewe and goat cheese whey. All CMPs showed a higher foaming capacity (140-180 mL) than WPC (120-150 mL) independent of conditions. These results could be affected by the presence of inhibitory compounds (fat and lactose) in the WPC, partially or totally removed during isolation procedure in the CMP and to the small molecular weight of the CMP peptide compared with the WPC. Foaming capacity of WPC and CMPs showed a significant dependence on pH and, to a lesser degree, on protein concentration and ionic strength. All the samples exhibited the highest foaming values at alkaline pH and minimum values at acid pH, increasing with protein concentration. Foam stability values were higher for CMP solutions than for WPC. The latter showed similar stability values as CMPs in acid pH conditions (<85%), however, at alkaline pH WPC lost more than 30% while CMPs showed no significant dependence on pH. Foam stability of the different CMP solutions could not be correlated with the variables pH, ionic strength and protein concentration; whereas pH and protein concentration influenced the stability of WPC foams.Peer Reviewe

Viscoelastic properties of caseinmacropeptide isolated from cow, ewe and goat cheese whey

Caseinmacropeptide (CMP) is a C-terminal glycopeptide released from κ-casein by the action of chymosin during cheese-making. It is recognised as a bioactive peptide and is thought to be an ingredient with a potential use in functional foods. CMP occurs in sweet cheese whey and whey protein concentrate (WPC). Its composition is variable and depends on the particular whey source and the fractionation technology employed in the isolation. There were no significant (P 5 min) than the CMPs (20°) phase angle than CMP (<20°), which could be associated with untidy structures, limiting elastic properties of the gel. © 2006 Society of Chemical Industry.This work was supported by the National ResearchPlan (Project ALI98-0969-C02-02).Peer Reviewe