Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation

Abstract

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. Methods: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6−/− MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. Results: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. Conclusion: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.

sNASP Mutation Aggravates to the TLR4-Mediated Inflammation in SLE by TAK1 Pathway

“…Cytokine dysregulation aggravates immune dysfunction, leading to autoimmune diseases such as SLE [ 33 ]. The pro-inflammatory cytokines, which infer IL-6 as a mediator of disease initiation, increase the susceptivity of the vascular pathology in MRL-Fas lpr mouse model [ 34 ]. A meta-analysis suggested that the levels of IL-6 and TNF- α in SLE patients were higher than in healthy controls [ 35 ].…”

Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies

“…The increase in the proliferation of B-GCs by PRL also resulted in an increase in the percentage of IL6+ cells, and elevated concentrations of IL-6 in the serum of mice and supernatants of differentiated B-GCs correlated with high PRL concentrations. IL-6 serum levels are markedly increased in mice with autoimmunity ( 25 , 49 ), and human patients with SLE ( 50 , 51 ). IL-6 is required for the GC formation because it facilitates the expression of master regulator BCL6 in helper follicular T-cell differentiation.…”

Connection between Celiac Disease and Systemic Lupus Erythematosus in Children—A Development Model of Autoimmune Diseases Starting from What We Inherit to What We Eat

“…Inflammation is also a common characteristic of the two conditions and is found in particular in the composition of each in the form of a pro-inflammatory intestinal environment, which leads to an expansion of gliadin-specific T cells (in people with genetic sensitivity) and the perpetuation of a pro-inflammatory phenotype in the case of CD, or, on the contrary, of a vascular inflammation mediated by IL-6 found in SLE, which has as a consequence the appearance of perivascular and vascular leukocyte infiltration and vascular dysfunction with the implicit increase in cardiovascular mortality [28,29].…”