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The migration of immune cells from one organ to another is critical for their differentiation and function1,2. T cells play critical roles in multiple sclerosis, a human disease characterized by the demyelination of neurons and detrimental damage to the nervous system3. The lung is involved in this process by accumulating myeloid cells and educating myelin-reactive T cells to be more susceptible to disease development4,5. However, it remains to be explored whether processes in the lung can be used for therapeutic interference.
Here, we report that [Pyr1]-Apelin 13 (A13) treatment leads to reduced disease development and severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Following A13 treatment, immune cell entry into the brain was strongly reduced, whereas immune cell accumulation in the lung was further increased. Further arguing for a primary effect of A13 in the lung, the receptor for Apelin, APJ, shows strong expression in adult pulmonary endothelial cells (ECs) but not in brain ECs.
Investigation of A13 effects on ECs reveals that A13 treatment reduces inflammatory gene expression of ECs in vitro and in vivo. In addition, APJ-expressing ECs show weaker VE-Cadherin+ junctions than other ECs, whereas A13 treatment increases junctional VE-Cadherin together with the internalization of the APJ. These changes significantly hamper immune cell trafficking as well as proper clustering formation.
Based on the sum of our data, we propose a beneficial effect of A13 treatment in the development of autoimmune disease through the alteration of immune cell clustering and trans-endothelial cell migration in the lung. These results suggest the lung as a novel therapeutic target for neurological autoimmune diseases.
References
1 Masopust, D. & Schenkel, J. M. The integration of T cell migration, differentiation and function. Nat Rev Immunol 13, 309-320 (2013). https://doi.org:10.1038/nri3442
2 Luster, A. D., Alon, R. & von Andrian, U. H. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6, 1182-1190 (2005). https://doi.org:10.1038/ni1275
3 Goverman, J. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9, 393-407 (2009). https://doi.org:10.1038/nri2550
4 Odoardi, F. et al. T cells become licensed in the lung to enter the central nervous system. Nature 488, 675-679 (2012). https://doi.org:10.1038/nature11337
5 Vijitha, N. & Engel, D. R. Remote control of Th 17 responses: The lung-CNS axis during EAE. J Leukoc Biol 105, 827-828 (2019). https://doi.org:10.1002/JLB.1CE0219-072R
| Keywords | Lung, Vascular, Immune, Neurological autoimmune diseas, Apelin |
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