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An unprecedented O-fused ring 5,7-dihydroxy-4-methyl-2,2,3-triphenylbenzofuran-6(2H)-one (3) was first time synthesized. Further, a series of novel dialkyl/fluoroalkyl derivatives of compound 3, 5,7-dialkoxy/fluoroalkoxy-4-methyl-2,2,3-triphenylbenzofuran-6(2H)-one, were obtained with noninvasive fluorescence switching characteristics and aggregation-induced emission properties. Compared with fluoroalkyl derivatives, the alkyl analogs exhibited a significant bathochromic shift in solid-state fluorescence emission. Notably, these noninvasive fluorescent molecular switches could be facilely tuned through light and heat stimulation, which successfully achieved high contrast and reversible fluorescent emission between orange and yellow endowing them with potential applications in data encryption materials. In addition, the single crystal data of compounds 3and 7-CF3displayed weak intermolecular interactions in different directions, resulting in twisted conformation and antiparallel slip stacking. Interestingly, the polymer dimethyl silicone film doped with 7-C3F7also showed an evident light-responsive behavior, meeting the criterion for fluorescent materials in the optical field.

ADAM17 regulates CXCR2 surface levels in circulating neutrophils and their infiltration into sites of inflammation. The chemokine receptor CXCR2 is expressed at high levels on circulating neutrophils and is critical for directing their migration to sites of inflammation. CXCR2 surface levels are rapidly modulated by 2 mechanisms—cell internalization and recycling upon ligand binding—and by a metalloprotease activity following overt neutrophil activation by nonligand stimuli. The latter process has only been described in human neutrophils, and essentially, nothing is known about its functional relevance and the specific protease involved. We show that targeting ADAM17 in mouse and human neutrophils blocks CXCR2 down‐regulation induced by nonligand stimuli but not by chemokine ligands. This was determined by use of a selective ADAM17 inhibitor, an ADAM17 function‐blocking antibody, and ADAM17 gene‐targeted mice. CXCR2 is known to undergo a marked down‐regulation during various inflammatory disorders, and this is associated with impaired neutrophil recruitment. We show that blocking ADAM17 activity reduced CXCR2 down‐regulation on circulating neutrophils and enhanced their recruitment during acute inflammation, which was reversed by a CXCR2 inhibitor. Taken together, our findings demonstrate that unlike CXCR2 internalization, ADAM17 induction down‐regulates the receptor in an irreversible manner and may serve as a master switch in controlling CXCR2 function, but may also contribute to neutrophil dysfunction during excessive inflammation.

ADAM17 functions as a molecular rheostat to control neutrophil influx at sites of infection by regulating the surface density of L‐selectin. Neutrophil infiltration and bacterial clearance occur earlier in conditional knockout mice with leukocytes lacking the metalloprotease ADAM17 than in control mice. We investigated cell‐intrinsic changes in neutrophils lacking ADAM17 and alterations in the inflammatory environment in conditional ADAM17 knockout mice to determine how the sheddase exerts its effects on neutrophil recruitment. In vivo analyses comparing control and ADAM17‐deficient neutrophils revealed that the latter cells accumulated at increased levels in the inflamed mesenteric microvasculature and in the peritoneal cavity following bacterial challenge, indicating changes in their adhesive properties. Consistent with this, bacterial infection caused a marked down‐regulation of L‐selectin, an adhesion protein and substrate of ADAM17, from the surface of circulating neutrophils in control mice but not in conditional ADAM17 knockout mice. Neutrophils from gene‐targeted mice with leukocytes expressing a noncleavable form of L‐selectin also displayed a competitive advantage in the presence of control neutrophils when infiltrating a site of infection. Taken together, our findings reveal that impaired L‐selectin shedding is a key mechanism underlying early neutrophil recruitment in conditional ADAM17 knockout mice during bacterial infection. Disrupting only the shedding of L‐selectin, however, did not increase bacterial clearance, indicating that additional substrates also contribute to the detrimental role of ADAM17 during severe infection.

A novel in vivo role for ADAM17 in modulating inflammation and host resistance against a Gram‐negative bacterial infection. Inflammation is the body's initial response to infection, which is harmful when excessive, as exemplified in sepsis inflammatory syndromes. Ectodomain shedding by the membrane metalloprotease ADAM17 is an emerging regulator of inflammation, as it directs the activity of various inflammatory modulators. At this time, however, little is known about the in vivo function of ADAM17. Here, we show that ADAM17‐deficient leukocytes afforded mice a survival benefit following Escherichia coli‐mediated peritoneal sepsis, which was associated with a reduction in systemic proinflammatory cytokine levels and bacterial burden. A more rapid yet transitory neutrophil infiltration into the peritoneal cavity of conditional ADAM17 knockout mice was observed when compared with control mice, suggesting a mechanism for their enhanced clearance of bacteria. Preventing the shedding of L‐selectin augments neutrophil recruitment, and we show that L‐selectin shedding by peritoneal neutrophils in conditional ADAM17 knockout mice was impaired. Moreover, their peritoneal TNF‐α levels were markedly lower than control mice following E. colichallenge. These events indicate key molecular processes involved in the altered time course of neutrophil recruitment in conditional ADAM17 knockout mice. Overall, our study provides novel in vivo evidence of the instrumental role of ADAM17 in modulating inflammation and host resistance during Gram‐negative bacterial infection.