Research Article: MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus

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.

http://doi.org/10.1371/journal.pone.0181015

Abstract

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.

Partial Text

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 [28].

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 [28]. A further understanding of the role of miRNAs, and miR155 in particular, might allow for the identification of a new therapeutic strategy in SLE.

 

Source:

http://doi.org/10.1371/journal.pone.0181015

 

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