SSPs reduce extravasation of immune cells towards psoriatic dermis in mouse skin.
Restoring peripheral immune tolerance and preventing destructive autoimmune reactions are crucial functions of the immune system, with dendritic cells (DCs) playing a pivotal role. DCs not only initiate immune responses against pathogens but also sustain immune tolerance towards self-antigens. A persistent imbalance in peripheral immune tolerance is linked to the onset of autoimmune diseases. Consequently, reactivating the body’s own mechanisms to restore the disturbed immunological balance seems to be an ideal approach to prevent the development of autoimmune diseases.
Researchers from the Westfaelische Wilhelms-University of Muenster have made significant strides in understanding the natural regulation of peripheral immune tolerance by the spleen. Their findings indicate that a subset of Small Spleen Peptides (SSPs) influences the differentiation of dendritic cells by modulating extracellular ATP synthesis. This groundbreaking research, led by Dr. Viktor Wixler, in collaboration with Dr. Rafael Dantas, Dr.Georg Varga, Dr. Yvonne Boergeling, and Professor Stephan Ludwig, has been published in the journal Biomolecules.
The team’s research demonstrates the significant potential of SSPs to restore peripheral immune tolerance, a crucial aspect in managing autoimmune diseases. According to Dr. Wixler, “Our previous research demonstrated that small spleen peptides can effectively prevent the progression of developing or established psoriatic arthritis, even in the persistent presence of high levels of the pro-inflammatory cytokine TNFα. Moreover, our studies have shown that DCs, which are pivotal in maintaining immunological balance, are primarily influenced by SSPs and transformed into tolerogenic cells, fostering the development of immunosuppressive Treg cells.”
In their recent study, the researchers identified thymosins as the main constituents of SSPs, with thymosin beta 4 (Tβ4) emerging as the most prevalent peptide. Intriguingly, recombinant thymosin was less efficient in inhibiting arthritis compared to the natural SSP mix. The team hypothesized that SSPs regulate extracellular ATP (exATP) profiles. Real-time investigation unveiled that tolerogenic stimulation with SSPs led to robust de novo exATP synthesis followed by significant degradation, while immunogenic stimulation resulted in less pronounced increases and degradation of exATP.
This modulation of exATP profiles was found to be crucial in determining the fate of DCs towards an inflammatory or tolerogenic state. Of significance in this context is the ATP degradation product adenosine, recognized as a key tolerogenic stimulus. Consistent with this, and the in vivo anti-inflammatory impact of SSPs, the team’s research demonstrated that the tolerogenic properties of SSPs are primarily influenced by adenosine receptors. Additionally, in vivo administration of SSPs was shown to suppress psoriatic skin inflammation, further underlining their therapeutic potential. Dr. Wixler emphasized, “The activation of adenosine receptors significantly influences gene transcription and regulates various cellular processes, including vascular tone, tissue damage and repair, as well as neuroinflammatory reactions and inflammation.”
In summary, the research of Dr. Wixler and colleagues underscores the significance of SSPs as natural regulators of peripheral immunological tolerance. Their findings offer essential insights into how SSPs shape dendritic cell differentiation through modulation of extracellular ATP synthesis, paving the way for new therapeutic strategies in treating autoimmune diseases.
Journal Reference
Wixler, V.; Leite Dantas, R.; Varga, G.; Boergeling, Y.; Ludwig, S. Small Spleen Peptides (SSPs) Shape Dendritic Cell Differentiation through Modulation of Extracellular ATP Synthesis Profile. Biomolecules 2024, 14, 469. DOI: https://doi.org/10.3390/biom14040469
About The Author
Dr. Viktor Wixler pursued a degree in biology and obtained his PhD in Novosibirsk, Russia. His career took him to various scientific institutions around the world, from renowned labs to less well-known ones in Asia, America, and Europe. Throughout his academic journey, his main focus has revolved around tumor immunology, autoimmune diseases, and molecular cell biology. For the past two decades, he served as an associate professor at the University of Münster in Germany. Since officially retiring four years ago, he has rekindled his passion for hands-on laboratory work, spending his days standing at the bench and pipetting, often working independently. This rediscovered old commitment was also the catalyst for the creation of this paper.
