Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation

The causative role of inflammation in hypertension-related cardiovascular diseases is evident and calls for development of specific immunomodulatory therapies. We tested the therapeutic efficacy and mechanisms of action of developmental endothelial locus-1 (DEL-1), an endogenous anti-inflammatory factor, in angiotensin-II (ANGII)- and DOCA (deoxycorticosterone acetate)-salt-induced cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1) and performing preventive and interventional studies by injecting recombinant DEL-1 in mice, we showed that DEL-1 improved endothelial function and abrogated aortic adventitial fibrosis, medial thickening and loss of elastin. DEL-1 also protected the mice from cardiac concentric hypertrophy, interstitial and perivascular coronary fibrosis and improved left-ventricular function and myocardial coronary perfusion. DEL-1 prevented aortic stiffness and abolished the progression of hypertension. Mechanistically, DEL-1 acted by inhibiting αvβ3-integrin dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized αvβ3-integrin dependent CD25+FoxP3+ Treg numbers and IL-10 levels, which were associated with decreased pro-inflammatory cell recruitment of inflammatory cells and reduced production of pro-inflammatory cytokines in cardiovascular organs. The demonstrated effects and immune-modulating mechanisms of DEL-1 in abrogation of cardiovascular remodeling and progression of hypertension identify DEL-1 as a potential therapeutic factor

Defensiny a autoimunita: Nový model využívající alfa-defensiny pro studium mechanismů autoimunitních dějů

The process of immune "self-nonself discrimination" is of utmost importance for the survival of all species as the biodestructive force of immune system can be directed towards the host as much as to pathogens. Thus, to shift this balance towards the latter, T cells bearing self- recognizing receptors are removed in the thymus (central tolerance) or their reactivity is harnessed through various additional mechanisms in periphery (peripheral tolerance). If the selfreactive T cells are not deleted and persist in the body, the regulation of self-tolerance can be breached, leading to the onset of autoimmunity. Presented thesis revolved around α-defensins, very effective bactericidal peptides that represent an important part of humoral innate immunity. There are two types of α-defensins: myeloid, expressed predominantly in neutrophils, and enteric, synthesized by intestinal Paneth cells. Data presented inhere are first to characterized the involvement of α-defensin- expressing cells in two types of autoimmune diseases, insulin-dependent diabetes mellitus (T1D) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). The former relates to the identification of transcriptionally activated myeloid α-defensin- expressing eosinophils present in the thymus of diabetes prone rat. In...Základní vlastností imunitního systému je jeho schopnost rozlišit tělu "vlastní" tkáně od "cizích", patogenních struktur. Na zajištění tolerance vůči tělu vlastním strukturám se podílejí mechanismy jak centrální (probíhající v primárních lymfatických orgánech), tak periferní tolerance. Selhání centrální tolerance v thymu tedy poruchy odstranění autoreaktivních T- lymfocytů vede posléze k jejich uvolnění na periferii. Je známo, že tato skutečnost napomáhá vzniku celé řady autoimunit. Nezanedbatelnou součást humorální vrozené imunity tvoří α-defensiny, velmi účinné baktericidní peptidy. Jsou známy dvě skupiny α-defensinů-myeloidní, vyskytující se převážně v neutrofilech a enterické, produkované zvláštním typem střevních tzv. Panethových buněk. Prezentovaná data poukazují na spojitost defensinů a jejich buněčného zdroje s průběhem dvou autoimunitnich chorob, diabetu 1. typu a tzv. APECED syndrom (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). V prvním případě výsledky odhalují přítomnost transkripčně aktivních eosinofilů produkujících α-defensiny v thymu u diabetických potkanů. Aktivované eosinofily exprimující α-defensiny byly také detekovány v kapilární krvi u pacientů s diabetem, přičemž tento fenomén se netýkal eosinofilů získaných od zdravých jedinců. Dále výsledky mikročipové...Department of Cell BiologyKatedra buněčné biologieFaculty of SciencePřírodovědecká fakult

Defensins and autoimmunity: emerging alpha-defensin based model to study mechanisms underpinning autoimmune processes

The process of immune "self-nonself discrimination" is of utmost importance for the survival of all species as the biodestructive force of immune system can be directed towards the host as much as to pathogens. Thus, to shift this balance towards the latter, T cells bearing self- recognizing receptors are removed in the thymus (central tolerance) or their reactivity is harnessed through various additional mechanisms in periphery (peripheral tolerance). If the selfreactive T cells are not deleted and persist in the body, the regulation of self-tolerance can be breached, leading to the onset of autoimmunity. Presented thesis revolved around α-defensins, very effective bactericidal peptides that represent an important part of humoral innate immunity. There are two types of α-defensins: myeloid, expressed predominantly in neutrophils, and enteric, synthesized by intestinal Paneth cells. Data presented inhere are first to characterized the involvement of α-defensin- expressing cells in two types of autoimmune diseases, insulin-dependent diabetes mellitus (T1D) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). The former relates to the identification of transcriptionally activated myeloid α-defensin- expressing eosinophils present in the thymus of diabetes prone rat. In..