Paracellular and Transcellular Leukocytes Diapedesis Are Divergent but Interconnected Evolutionary Events.


Mickael ME(1)(2), Kubick N(3), Klimovich P(2), Flournoy PH(2), Bieńkowska I(1), Sacharczuk M(1)(4).
Author information:
(1)Department of Experimental Genomics, Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Postępu 36A, 05-552 Jastrzebiec, Poland.
(2)Department of Immunology, PM Forskningscentreum, 17854 Ekerö Stockholm, Sweden.
(3)Department of Biochemistry and Molecular Cell Biology
(IBMZ), University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
(4)Department of Pharmacodynamics, Faculty of Pharmacy, Warsaw Medical University, l Banacha 1, 02-697 Warsaw, Poland.


Infiltration of the endothelial layer of the blood-brain barrier by leukocytes plays a critical role in health and disease. When passing through the endothelial layer during the diapedesis process lymphocytes can either follow a paracellular route or a transcellular one. There is a debate whether these two processes constitute one mechanism, or they form two evolutionary distinct migration pathways. We used artificial intelligence, phylogenetic analysis, HH search, ancestor sequence reconstruction to investigate further this intriguing question. We found that the two systems share several ancient components, such as RhoA protein that plays a critical role in controlling actin movement in both mechanisms. However, some of the key components differ between these two transmigration processes. CAV1 genes emerged during Trichoplax adhaerens, and it was only reported in transcellular process. Paracellular process is dependent on PECAM1. PECAM1 emerged from FASL5 during Zebrafish divergence. Lastly, both systems employ late divergent genes such as ICAM1 and VECAM1. Taken together, our results suggest that these two systems constitute two different mechanical sensing mechanisms of immune cell infiltrations of the brain, yet these two systems are connected. We postulate that the mechanical properties of the cellular polarity is the main driving force determining the migration pathway. Our analysis indicates that both systems coevolved with immune cells, evolving to a higher level of complexity in association with the evolution of the immune system.