Cross-talk between endocytic clearance and secretion in macrophages

Macrophages are essential elements of innate immunity that control inflammatory reactions, healing processes, tissue homeostasis and immune tolerance by the co-ordinated release and clearance of soluble mediators. Scavenger receptors (SRs) constitute a major class of receptors, which direct endocytosed material for degradation. SR-mediated uptake can result in both pro-inflammatory and tolerogenic programming of macrophages. While effects of SRs on the level of signal transduction are well documented, the effect of endocytosis on the regulated secretion, in particular lysosomal secretion, in macrophages remains to be elusive. Stabilin-1, SR identified and functionally characterized by us, mediates clearance of acLDL and universal regulator of tissue turn-over - SPARC. Unexpectedly for SRs, stabilin-1 shuttles between endosomal compartment and biosynthetic compartment and transports newly synthesized stabilin-interacting chitinase-like protein (SI-CLP) to the lysosomal secretory pathway. This sorting function of stabilin-1 is mediated by GGAs, clathrin adaptors responsible for the mannose-6-phosphate receptors (MPR)-mediated transport of lysosomal hydrolases. Moreover, stabilin-1 internalizes hormone placental lactogen, transports it to the trans-Golgi network-associated transcytosis. Thus stabilin-1 is the only known SR that links endocytic clearance, intracellular sorting and trancytosis. We propose novel level of regulation for the secretory repertoire of macrophages: cross-talk of uptake and release at the level of vesicular trafficking.