Lymphocyte migration

CLEVER-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium. Salmi, M. et al. Blood 104, 3849–3857 (2004).

Lymphocyte trafficking from the blood to the tissues has been extensively studied and is described by the multistep adhesion cascade. By contrast, the mechanism used by lymphocytes to cross lymphatic-vessel walls is much less well understood. Salmi and colleagues show that the glycoprotein CLEVER1 (common lymphatic endothelial and vascular endothelial receptor 1) is constitutively expressed on lymphatic endothelial vessels, and its expression is upregulated by inflamed vascular endothelial cells. CLEVER1 can mediate the adhesion and migration of lymphocytes (and the adhesion of tumour cells) through lymphatic-vessel walls, as well as through blood-vessel walls, under physiologically relevant shear forces. CLEVER1 is therefore a potential target for the development of new therapies for inflammation and cancer.

HIV

Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection. Ma, G. et al. J. Exp. Med. 200, 1337–1346 (2004).

One of the earliest identified functions of the serine-protease inhibitor SLPI (secretory leukocyte protease inhibitor) was as an inhibitor of HIV-1 infection of macrophages. However, the identity of the cell-surface receptor for SLPI is unknown. This study shows that the phospholipid-binding protein annexin II is a receptor for SLPI. Inhibitors of annexin II mimicked the kinetics of action of HIV-1 suppression by SLPI, indicating a connection. The authors identified annexin II as a fusogenic cofactor for HIV-1 infection and a possible target for new therapeutics: HIV-1 can bind annexin II through phosphatidylserine molecules in the HIV-1 envelope, which are acquired from the host during viral exit from infected cells.

Macrophages

IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism. Stockinger, S. et al. J. Immunol. 173, 7416–7425 (2004).

Type I interferons (IFNs) produced by macrophages in response to infection with Listeria monocytogenes sensitize macrophages to L. monocytogenes-induced cell death. In this study, Stockinger et al. sought to determine the molecular mechanisms of the L. monocytogenes-mediated induction of genes that encode type I IFNs. IFN-α production by L. monocytogenes-infected macrophages was dependent on IFN-β production, and IFN-β production was dependent on the presence of IFN-regulatory factor 3 (IRF3). IFN-β production was not affected by the absence of the pathogen-recognition receptors Toll-like receptor 4 (TLR4), TLR9 or nucleotide-binding oligomerization domain protein 2 (NOD2), or of the adaptor molecules MyD88, TRIF or TRAF. So, the authors suggest that L. monocytogenes targets IRF3 through a new pathway, which is TLR and NOD2 independent.