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

Paul Marczynski,Myriam Meineck,Wilfried Roth,Julia Weinmann-Menke,Simone Boedecker,Andreas Schwarting,Tamara Möckel,Daniel Kraus,Ning Xia,Huige Li

doi:10.3390/ijms22052291

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.

Highlights

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease, affecting predominantly women in childbearing age, and kidney failure is a major cause of morbidity and mortality in these patients [1]
Even if the overall-cause of mortality for SLE decreased over the last decades, partly due to improvements in therapy and diagnosis, patients with SLE show increased overall-cause mortality rates and severely compromised quality of life compared to the general population [2,3]
An increase in leukocytes infiltrations was seen in MRL-Faslpr mice at 5 mo compared to 3 mo of age (Figure 1B)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease, affecting predominantly women in childbearing age, and kidney failure is a major cause of morbidity and mortality in these patients [1]. Even if the overall-cause of mortality for SLE decreased over the last decades, partly due to improvements in therapy and diagnosis, patients with SLE show increased overall-cause mortality rates and severely compromised quality of life compared to the general population [2,3]. Main causes of death for patients with SLE are renal and cardiovascular diseases (CVD), and infections [4]. In SLE patients, apart from stroke and end-stage kidney failure, CV mortality is highly increased Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality.

Methods

Results

Conclusion