Date Published: July 18, 2017
Publisher: Public Library of Science
Author(s): Harald Leiss, Wilhelm Salzberger, Barbara Jacobs, Irina Gessl, Nicolas Kozakowski, Stephan Blüml, Antonia Puchner, Attila Kiss, Bruno K. Podesser, Josef S. Smolen, Georg H. Stummvoll, Masataka Kuwana.
We herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced lupus.
Systemic lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes.
After induction of lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092±0.00015 vs. 0.0027±0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95±0.19 vs 3±0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF-signature (MX1, IP10, IRF7, ISG15).
MiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE.
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with abnormal activity of both the adaptive and innate immune systems. Its clinical presentations range from mild musculoskeletal discomfort to life-threatening multiple organ involvement [1, 2].
Given that the etiology of SLE has not been fully elucidated, current therapies, although effective in many cases, still show major limitations. MiR155, as a molecule potentially involved in lupus pathogenesis, might constitute an interesting therapeutic target .
Since despite all efforts still many SLE patients do not sufficiently respond to current concepts of therapy and since the application of a miR155 antagomir could reduce early diffuse alveolar hemorrhage (DAH) in experimental lupus, miR155 might become an interesting aspect in treating (refractory) lupus . A further understanding of the role of miRNAs, and miR155 in particular, might allow for the identification of a new therapeutic strategy in SLE.