Role of the long non-coding RNA lincRNA-LUCAT1 in a murine model of systemic lupus erythematosus

• Applicant: Dr. Tim Vierbuchen
• Subject Area: Immunology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418082105

The immune system has evolved to defend the body from invading pathogens and abnormal endogenous cells while healthy cells should be protected from excessive immune responses. Therefore, a tight regulation of immune reactions is fundamental. Recent studies have shown that besides proteins and microRNAs, long non-coding RNAs (lncRNAs) possess an important role in the regulation of immune genes. However, the function of most lncRNAs and their role in inflammatory diseases remains elusive. The long intergenic non-coding RNA LUCAT1 (lincRNA-LUCAT1) is upregulated after activation of several innate immune receptors and negatively regulates the expression of pro-inflammatory and interferon stimulated genes. Human phagocytes deficient in LUCAT1 show significantly increased expression of immune regulated genes particularly interferon-stimulated genes (ISGs) after stimulation while overexpression of LUCAT1 in THP1 or pulmonary epithelial cells leads to suppression of LPS or virus induced interferon responses. The levels or LUCAT1 are also lower in systemic lupus erythematosus (SLE) patients. Yet, the role of LUCAT1 in vivo and its contribution to autoimmune disorders is currently unknown. This study aims to elucidate the in vivo functions of LUCAT1 through characterization of a LUCAT1-deficient mouse and to investigate the contribution of LUCAT1 to SLE. The ability of LUCAT1 to restrain immune responses may have a protective effect on the pathogenesis of SLE. Moreover, we will analyze if the anti-inflammatory metabolite itaconate is able to induce LUCAT1 expression through activation of the transcription factor Nrf2. Since LUCAT1 is a potent repressor of immune responses in myeloid cells, it may be an attractive target for newly developed RNA therapeutics for the treatment of autoimmunity and sterile inflammation.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Katherine A. Fitzgerald, Ph.D.