TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury.

BACKGROUND: Necroptosis of macrophages is a necessary element in reinforcing intrapulmonary inflammation during acute lung injury (ALI). However, the molecular mechanism that sparks macrophage necroptosis is still unclear. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor expressed broadly on monocytes/macrophages. The influence of TREM-1 on the destiny of macrophages in ALI requires further investigation. METHODS: TREM-1 decoy receptor LR12 was used to evaluate whether the TREM-1 activation induced necroptosis of macrophages in lipopolysaccharide (LPS)-induced ALI in mice. Then we used an agonist anti-TREM-1 Ab (Mab1187) to activate TREM-1 in vitro. Macrophages were treated with GSK872 (a RIPK3 inhibitor), Mdivi-1 (a DRP1 inhibitor), or Rapamycin (an mTOR inhibitor) to investigate whether TREM-1 could induce necroptosis in macrophages, and the mechanism of this process. RESULTS: We first observed that the blockade of TREM-1 attenuated alveolar macrophage (AlvMs) necroptosis in mice with LPS-induced ALI. In vitro, TREM-1 activation induced necroptosis of macrophages. mTOR has been previously linked to macrophage polarization and migration. We discovered that mTOR had a previously unrecognized function in modulating TREM-1-mediated mitochondrial fission, mitophagy, and necroptosis. Moreover, TREM-1 activation promoted DRP1Ser616 phosphorylation through mTOR signaling, which in turn caused surplus mitochondrial fission-mediated necroptosis of macrophages, consequently exacerbating ALI. CONCLUSION: In this study, we reported that TREM-1 acted as a necroptotic stimulus of AlvMs, fueling inflammation and aggravating ALI. We also provided compelling evidence suggesting that mTOR-dependent mitochondrial fission is the underpinning of TREM-1-triggered necroptosis and inflammation. Therefore, regulation of necroptosis by targeting TREM-1 may provide a new therapeutic target for ALI in the future.

Point-spread imaging for measurement of skin translucency and scattering.

BACKGROUND/PURPOSE: The translucency of skin has long been identified as an important cue for healthy and youthful looking skin. There is currently no universal definition for skin translucency let alone a measurement method. We propose that skin translucency is the light scattering beneath skin surface. We demonstrate the use of polarization gated point spreading imaging for non-invasive, in vivo measurement of the translucency and the reduced scattering coefficient m's of skin. METHODS: We developed a polarization-gated point-spread imaging system to measure the spread of the incident pencil-thin laser beam on the skin. Skin translucency was calculated as the spread of the laser beam. From the measurement of the shift of the light diffuse center from the light injection point, the reduced scattering coefficient m's of the skin was calculated. We validated the measurement technique with milk as an in vitro model for skin. RESULTS AND CONCLUSION: The measured m's of milk solution was found to be linearly proportional to the milk concentration, in agreement with Beer's law. The calculated translucency decreased as the milk concentration increased or as the reduced scattering coefficient m's increased. It was also found that the translucency decreased as the absorption coefficient of the milk solution increased. The measured translucency of a set of custom made clay tiles correlated well with the consumer perception of the incremental ranking of the translucency. In vivo measurement of skin translucency and the reduced scattering coefficient m's were carried out on several volunteers. The measured reduced scattering coefficient m's was in agreement with those in the literature. The measured skin translucency for different skin ethnicities of Caucasian, North Asian, South Asian and African American were in line with the expectation that skin translucency decreases as the skin color gets darker.