Emerging roles for ectodomain shedding in the regulation of inflammatory responses

Abstract

The multistep model of leukocyte recruitment to sites of inflammation has helped elucidate specific molecular cues for each of the individual steps. However, it is less clear how cells transition between the different steps and how the complex interactions are coordinately regulated. Once a leukocyte sticks to the endothelium, it only takes a few minutes to reach the subendothelial basement membrane, so the transitions and regulatory mechanisms must be rapid. We put forward the hypothesis that proteolytic shedding of cell surface proteins provides a mechanism to aid in the rapid transition of cells and coordinate the complex, multistep process of leukocyte recruitment in response to inflammatory stimuli. Support for this hypothesis is provided from analyses of disease states and from studies with protease inhibitors and genetically engineered mutations that prevent "ectodomain shedding" of cell surface proteins and consequently perturb the inflammatory response.

Site‐specific N‐glycosylation regulates the GPS auto‐proteolysis of CD97

“…Post-translational modification by proteolytic cleavage has been recognized as an important mechanism for the functional modulation of a diverse array of cell surface proteins, such as Notch, protease-activated receptors (PARs) and many cell adhesion molecules [1][2][3]. Proteolytic modification of these molecules usually takes place in the secretory pathway or on the cell surface, mediated by proprotein convertases or sheddases such as furin, MMPs and ADAMs [4].…”

Metalloproteinase-mediated Shedding of Integrin β2 Promotes Macrophage Efflux from Inflammatory Sites

“…Both the pro-and active forms of MMP-9 have previously been demonstrated in peritoneal fluid following thioglycollate injection (19). Peritoneal fluid from mice deficient in myeloid ADAM10 and ADAM17, two enzymes that have been shown to shed many cell surface proteins (6,20), was also tested (Table 1), and their deletion also did not significantly alter shedding of integrin ␤2. The decreased efficiency of GM6001-mediated blockade of soluble integrin ␤2 shedding from MMP-9 null macrophages suggests that increased levels of nonmetalloproteinase enzymes may compensate for the loss of MMP-9.…”

“…Macrophages-We have proposed that proteolytic shedding of cell surface proteins contributes to regulation of leukocyte recruitment to inflammatory stimuli (6). To characterize properties of cleaved integrin ␤2 identified in macrophage proteomics screens, elicited mouse peritoneal macrophages (stimulated to emigrate into the peritoneal cavity by injection of the sterile irritant thioglycollate) were harvested 4 days after thioglycollate and activated in vitro with different stimuli.…”

“…Although integrin proteolysis has not been shown to regulate leukocyte trafficking, cleavage of another adhesion molecule, L-selectin, selectively limits early neutrophil influx (5). Shedding of other adhesion molecules can also elicit rapid changes in cellular responses, instantly lower adhesion molecule density, and release soluble forms of their extracellular domains that can act as antagonists (6,7). In an effort to detect novel proteins proteolytically cleaved from the surface of inflammatory macrophages, we identified the extracellular domain of integrin ␤2 in two proteomic screens using different inflammatory stimuli (8).…”

Transmembrane chemokines: Versatile ‘special agents’ in vascular inflammation

“…These other substratesfor ADAM-mediated shedding arealso expressed on the surfaceofendothelial cells or leukocytes and increasing evidences uggests their involvement in atherosclerosis. Inhibition of shedding enzymesw ould not onlya ffect the activity of transmembrane chemokinesbut also that of cytokines and adhesion molecules (121). In contrasttoinhibitors for chemokine receptors that specificallyb lockthe recruitment of their responsive leukocyte subsets, specifici nhibitors for shedding enzymes could potentiallyblockanumber of atherogenic processesa sw ella sv ascular remodeling but againhavetobecarefullymonitored for their side effects.…”