SSPs reduce immune cell extravasation into the psoriatic dermis in mouse skin.
Restoring peripheral immune tolerance and preventing destructive autoimmune reactions are crucial functions of the immune system, in which dendritic cells (DCs) play a pivotal role. DCs not only initiate immune responses against pathogens but also maintain 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 altered immune balance appears to be an ideal approach to prevent the development of autoimmune diseases.
Researchers at Westphalian Wilhelms University Münster have made significant progress in understanding the natural regulation of peripheral immune tolerance by the spleen. Their findings indicate that a subset of small splenic peptides (SSPs) influence dendritic cell differentiation by modulating extracellular ATP synthesis. This pioneering 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 the management of autoimmune diseases. According to Dr. Wixler, “Our previous research demonstrated that small peptides from the spleen 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. Furthermore, our studies have shown that dendritic cells, which are critical for maintaining immune balance, are primarily influenced by SSPs and transformed into tolerogenic cells, thereby promoting the development of immunosuppressive Treg cells.”
In their recent study, the researchers identified thymosins as the main components of SSPs, with thymosin beta 4 (Tβ4) found to be the most prevalent peptide. Interestingly, recombinant thymosin was less efficient in inhibiting arthritis compared to the natural SSP mixture. The team hypothesized that SSPs regulate extracellular ATP (exATP) profiles. Real-time investigation revealed that tolerogenic stimulation with SSPs led to robust de novo exATP synthesis followed by significant degradation, whereas immunogenic stimulation resulted in less pronounced exATP increases and degradation.
This modulation of exATP profiles was found to be crucial in determining the fate of dendritic cells towards an inflammatory or tolerogenic state. Important in this context is the ATP degradation product adenosine, which is recognised as a key tolerogenic stimulus. In line 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. Furthermore, in vivo administration of SSPs was shown to suppress psoriatic skin inflammation, further underlining their therapeutic potential. Dr Wixler emphasised: “Activation of adenosine receptors significantly influences gene transcription and regulates several 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 highlights the importance of SSPs as natural regulators of peripheral immune tolerance. Their findings offer essential insights into how SSPs shape dendritic cell differentiation through modulation of extracellular ATP synthesis, paving the way for novel therapeutic strategies in the treatment of autoimmune diseases.
Journal reference
Wixler, V.; Leite Dantas, R.; Varga, G.; Boergeling, Y.; Ludwig, S. Small splenic peptides (SSPs) shape dendritic cell differentiation through modulation of the extracellular ATP synthesis profile. Biomolecules 2024, 14, 469. DOI: https://doi.org/10.3390/biom14040469
About the Author
Dr. Viktor Wixler He studied biology and obtained his PhD in Novosibirsk, Russia. His career took him to various scientific institutions around the world, from renowned laboratories to lesser-known ones in Asia, America and Europe. Throughout his academic career, 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 practical laboratory work, spending his days standing at the workbench and pipetting, often working independently. This rediscovered old commitment was also the catalyst for the creation of this article.
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