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Publication : CaMKIα regulates AMP kinase-dependent, TORC-1-independent autophagy during lipopolysaccharide-induced acute lung neutrophilic inflammation.

First Author  Guo L Year  2013
Journal  J Immunol Volume  190
Issue  7 Pages  3620-8
PubMed ID  23447692 Mgi Jnum  J:194833
Mgi Id  MGI:5474890 Doi  10.4049/jimmunol.1102975
Citation  Guo L, et al. (2013) CaMKIalpha Regulates AMP Kinase-Dependent, TORC-1-Independent Autophagy during Lipopolysaccharide-Induced Acute Lung Neutrophilic Inflammation. J Immunol 190(7):3620-8
abstractText  Autophagy is an evolutionarily conserved cytoplasmic process regulated by the energy rheostats mammalian target of rapamycin and AMP kinase (AMPK) that recycles damaged or unused proteins and organelles. It has been described as an important effector arm of immune cells. We have shown that the cytoplasmically oriented calcium/calmodulin-dependent protein kinase (CaMK)Ialpha regulates the inflammatory phenotype of the macrophage (M). In this study, we hypothesize that CaMKIalpha mediates M autophagy. LPS induced autophagy in RAW 264.7 cells and murine peritoneal M that was attenuated with biochemical CaMK inhibition or CaMKIalpha small interfering RNA (siRNA). Inhibition of CaMKIalpha reduced LPS-induced p-Thr(172)AMPK and target of rapamycin complex-1 activity, and expression of a constitutively active CaMKIalpha but not a kinase-deficient mutant induced p-Thr(172)AMPK and autophagy that was attenuated by the AMPK inhibitor compound C. Coimmunoprecipitation and in vitro kinase assays demonstrated that CaMKIalpha activates AMPK, thereby inducing ATG7, which also localizes to this CaMKIalpha/AMPK complex. During LPS-induced lung inflammation, C57BL/6 mice receiving CaMKIalpha(siRNA) displayed reduced lung and bronchoalveolar immune cell autophagy that correlated with reduced neutrophil recruitment, myeloperoxidase activity, and air space cytokine concentration. Independently inhibiting autophagy, using siRNA targeting the PI3K VPS34, yielded similar reductions in lung autophagy and neutrophil recruitment. Thus, a novel CaMKIalpha/AMPK pathway is rapidly activated in M exposed to LPS and regulates an early autophagic response, independent of target of rapamycin complex-1 inhibition. These mechanisms appear to be operant in vivo in orchestrating LPS-induced lung neutrophil recruitment and inflammation.
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