All Roads Lead to Chang'An (条条大路通长安)

Managing systemic lupus erythematosus (SLE) can be a long and complex journey. Development of new therapeutic targets for SLE is an ongoing area of research. By repurposing existing compounds for treating SLE, we found that IRF4 might be the "Chang'An" in SLE treatment.
All Roads Lead to Chang'An (条条大路通长安)
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"All Roads Lead to Chang'An" is a famous saying that originated from ancient China. Chang'An was the capital city of many ancient Chinese dynasties, including the Han, Tang, and Sui dynasties. It was one of the most important cities in Chinese history and culture. The saying "All Roads Lead to Chang'An" reflects the historical significance and strategic location of the city. During ancient times, many important trade routes,including the Silk Road, passed through Chang'An. This made the city a hub for trade, culture, and exchange among different civilizations.
In the current study, we proposed interferon regulatory factor 4 (IRF4) as a "pathogenic hub"  in systemic lupus erythematosus (SLE), the highly complex and heterogeneous autoimmune disease with lupus nephritis (LN) as the common and dire manifestation. Findings in the study indicated a tight link between renal IRF4 level and disease progression both in LN patients and lupus-prone animals. Moreover, IRF4 expression is closely correlated with cellular and serological indicators of LN, and effective therapies in lupus-prone mice are accompanied with significant IRF4 decrease both in immune cells and kidney.

Picture was created by Midjourney AI Software 

    Firstly,  an investigation was conducted to analyze gene expression attributes in human kidney specimens, along with intervening experiments employing glucocorticoid prednisone (PNS) and artemisinin derivative SM934. The results obtained from this analysis highlighted significant evidence indicating IRF4 as a potentially promising therapeutic target for the treatment of SLE. 

     Furthermore, we investigated the potential prognostic and therapeutic relevance of IRF4 in murine models that spontaneously developed syndromes resembling human lupus. The results showed elevated renal IRF4 expression in lupus mice, along with strong correlations with disease progression markers.We also found that inhibiting IRF4 expression in T and B lymphocytes could effectively ameliorate renal dysfunction and autoantibody overproduction in SLE, leading to a promising strategy for SLE treatment by restricting pathogenic T and B cells responses.

        We proposed IRF4 as a competitive biomarker in SLE, especially in LN, based on the prominent expression of IRF4 in kidney tissue of SLE patients and lupus-prone mice and its tight link to disease progression and drug response. Albeit the correlation between autoantibodies and LN is clinically imprecise, our study indicated that ablating IRF4 expression in T and B lymphocytes could effectively ameliorate renal dysfunction and autoantibody overproduction respectively in SLE, thus providing a promising strategy for SLE treatment by restricting pathogenic T and B cells responses.

 Graphical summary of relationship among the IRF4 expression, pathogenic T and B cells responses, autoantibodies overproduction and renal dysfunction in SLE.

Welcome to read our origin article (DOI: 10.1038/s41392-023-01413-8) in Signal Transduction and Targeted Therapy for more information and email us (linzemin@gmail.com) to discuss the topic.

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