Schlafen-8 is essential for lymphatic endothelial cell activation in experimental autoimmune encephalomyelitis.

Schlafen-8 (Slfn8) is a member of the Schlafen family of proteins, which harbor helicase domains and are induced by LPS and interferons. It has been reported that the Schlafen family are involved in various cellular functions, including proliferation, differentiation and regulation of virus replication. Slfn8 has been implicated in T-cell differentiation in the thymus. However, the roles of Slfn8 in the immune system remains unclear. In this study, we generated Slfn8 knockout mice (Slfn8-/-) and investigated the immunological role of Slfn8 using the T-cell-mediated autoimmune model experimental autoimmune encephalomyelitis (EAE). We found that the clinical score was reduced in Slfn8-/- mice. IL-6 and IL-17A cytokine production, which are associated with EAE onset and progression, were decreased in the lymph nodes of Slfn8-/- mice. Immune cell populations in Slfn8-/- mice, including macrophages, neutrophils, T cells and B cells, did not reveal significant differences compared with wild-type mice. In vitro activation of Slfn8-/- T cells in response to TCR stimulation also did not reveal significant differences. To confirm the involvement of non-hematopoietic cells, we isolated CD45- CD31+ endothelial cells and CD45-CD31- gp38+ fibroblastic reticular cells by FACS sorting. We showed that the levels of IL-6 and Slfn8 mRNA in CD45- CD31+ endothelial cells were increased after EAE induction. In contrast, the level of IL-6 mRNA after EAE induction was markedly decreased in CD31+ endothelial cells from Slfn8-/- mice. These results indicate that Slfn8 may play a role in EAE by regulating inflammation in endothelial cells.

Membrane mechanisms for signal transduction: the coupling of the meso-scale raft domains to membrane-skeleton-induced compartments and dynamic protein complexes.

Virtually all biological membranes on earth share the basic structure of a two-dimensional liquid. Such universality and peculiarity are comparable to those of the double helical structure of DNA, strongly suggesting the possibility that the fundamental mechanisms for the various functions of the plasma membrane could essentially be understood by a set of simple organizing principles, developed during the course of evolution. As an initial effort toward the development of such understanding, in this review, we present the concept of the cooperative action of the hierarchical three-tiered meso-scale (2-300 nm) domains in the plasma membrane: (1) actin membrane-skeleton-induced compartments (40-300 nm), (2) raft domains (2-20 nm), and (3) dynamic protein complex domains (3-10nm). Special attention is paid to the concept of meso-scale domains, where both thermal fluctuations and weak cooperativity play critical roles, and the coupling of the raft domains to the membrane-skeleton-induced compartments as well as dynamic protein complexes. The three-tiered meso-domain architecture of the plasma membrane provides an excellent perspective for understanding the membrane mechanisms of signal transduction.