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AIM/CD5L Inhibits Resolution of Acute Lung Injury in Mice Through Efferocytosis Inhibition
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A2987 - AIM/CD5L Inhibits Resolution of Acute Lung Injury in Mice Through Efferocytosis Inhibition
Author Block: H. Kimura1, M. Suzuki1, S. Konno1, T. Nagase2, T. Miyazaki3, M. Nishimura1; 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan, 2Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 3Laboratory of Molecular Biomedicine for Pathogenesis, CDBIM, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Rationale: Apoptosis Inhibitor of Macrophage (AIM) is a multifaceted protein, which has been reported to be involved in lipid metabolism and a variety of inflammatory diseases (Miyazaki T, et al. J Exp Med 1999; Kurokawa J, et al. Cell Metab 2010; Sarrias MR, et al. J Biol Chem 2005; Arai S, et al. Nat Med 2016). In our previous analysis, we have shown that inflammatory resolution after LPS-induced lung injury was accelerated in AIM-knockout (KO) mice and that the process involved regulation of lipid mediator profile (Kimura H, et al. ATS conference 2014, 2016). Meanwhile, the detailed mechanism of how AIM exerts these effects remains unknown. Because inflammatory resolution is an active process involving macrophage efferocytosis of apoptotic neutrophils, we hypothesized that recombinant AIM protein (rAIM) may attenuate engulfment of apoptotic cells.
Aim: To elucidate the effect of rAIM on inflammatory resolution in vivo as well as in vitro.Methods: 50 μg/body of rAIM or bovine serum albumin (BSA) was administered intraperitoneally to AIM-KO mice with C57BL/6 background every other day from day -8 to day 4. 4 mg/kg of LPS was oropharyngeally administered on day 0. Wild type (WT) C57BL/6 mice were used as control. The mice were sacrificed and analyzed on day 5. In in vitro analysis, we pre-incubated bone marrow-derived macrophages from WT and AIM-KO mice and RAW 264.7 cells with 5 μg/ml of rAIM or BSA for 6 h following incubation with CFDA-labelled apoptotic neutrophils for 2 h. After washing and quenching extracellular fluorescence with Trypan blue, the numbers of engulfed cells were determined by monitoring fluorescence.
Results: The rAIM-treated AIM-KO mice had significantly higher number of BAL inflammatory cells than BSA-treated AIM-KO mice and the increased number was comparable to WT mice. In vitro analysis showed that the numbers of phagocytosed apoptotic neutrophils were lower when the macrophages were pre-incubated in the presence of rAIM in the three macrophage populations.
Conclusion: These data indicate that AIM in the extracellular milieu attenuates inflammatory resolution through efferocytosis inhibition.
Author Block: H. Kimura1, M. Suzuki1, S. Konno1, T. Nagase2, T. Miyazaki3, M. Nishimura1; 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan, 2Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 3Laboratory of Molecular Biomedicine for Pathogenesis, CDBIM, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Rationale: Apoptosis Inhibitor of Macrophage (AIM) is a multifaceted protein, which has been reported to be involved in lipid metabolism and a variety of inflammatory diseases (Miyazaki T, et al. J Exp Med 1999; Kurokawa J, et al. Cell Metab 2010; Sarrias MR, et al. J Biol Chem 2005; Arai S, et al. Nat Med 2016). In our previous analysis, we have shown that inflammatory resolution after LPS-induced lung injury was accelerated in AIM-knockout (KO) mice and that the process involved regulation of lipid mediator profile (Kimura H, et al. ATS conference 2014, 2016). Meanwhile, the detailed mechanism of how AIM exerts these effects remains unknown. Because inflammatory resolution is an active process involving macrophage efferocytosis of apoptotic neutrophils, we hypothesized that recombinant AIM protein (rAIM) may attenuate engulfment of apoptotic cells.
Aim: To elucidate the effect of rAIM on inflammatory resolution in vivo as well as in vitro.Methods: 50 μg/body of rAIM or bovine serum albumin (BSA) was administered intraperitoneally to AIM-KO mice with C57BL/6 background every other day from day -8 to day 4. 4 mg/kg of LPS was oropharyngeally administered on day 0. Wild type (WT) C57BL/6 mice were used as control. The mice were sacrificed and analyzed on day 5. In in vitro analysis, we pre-incubated bone marrow-derived macrophages from WT and AIM-KO mice and RAW 264.7 cells with 5 μg/ml of rAIM or BSA for 6 h following incubation with CFDA-labelled apoptotic neutrophils for 2 h. After washing and quenching extracellular fluorescence with Trypan blue, the numbers of engulfed cells were determined by monitoring fluorescence.
Results: The rAIM-treated AIM-KO mice had significantly higher number of BAL inflammatory cells than BSA-treated AIM-KO mice and the increased number was comparable to WT mice. In vitro analysis showed that the numbers of phagocytosed apoptotic neutrophils were lower when the macrophages were pre-incubated in the presence of rAIM in the three macrophage populations.
Conclusion: These data indicate that AIM in the extracellular milieu attenuates inflammatory resolution through efferocytosis inhibition.
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