LAUSR

Mounting evidence indicates that peripheral tissues and organs have inherent regulatory activity and impact on the host’s immune response; hence, they are not passive targets of inflammatory reactions. Indeed, tissue-derived homeostatic molecules can regulate the accumulation and functional plasticity of immune cells in order to maintain or restore tissue integrity [1,2]. This concept, which is integral to understanding tissue-specific immunity in steady-state and pathologies, is illustrated by research on the function of developmental endothelial locus-1 (DEL-1), a molecule that is secreted by tissue-resident cells (e.g., endothelial and mesenchymal stromal cells, and some macrophage subsets) [2]. DEL-1 is 52-kDa protein comprising three epidermal growth factor (EGF)-like repeats at the N-terminus and two discoidin I-like domains at the C-terminus, and is encoded by the EDIL3 (EGF-like repeats and discoidin I-like domains-3) gene (Figure 1). DEL-1 has the capacity to interact with distinct integrins, including β2 (e.g., αLβ2 and αMβ2) and αv (e.g., αvβ3) integrins, as well as phospholipids [2]. These interactions in turn enable DEL-1 to regulate important immune functions that have significant impact in inflammatory and autoimmune disorders in preclinical models [2], raising the possibility that DEL-1 may be a promising therapeutic target. DEL-1 is structurally similar with another integrin-binding protein, milk-fat-globule-EGF factor 8; although the two proteins share some functions, they are typically expressed by distinct cell subsets and regulated by different transcription factors, suggesting that they may often exert non-redundant biological activities [2].