| Autor: |
Buerger M; Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria., Amor M; Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria., Akhmetshina A; Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria., Bianco V; Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.; Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy., Perfler B; Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, 8010 Graz, Austria.; Division of Hematology, Medical University of Graz, 8010 Graz, Austria., Zebisch A; Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, 8010 Graz, Austria.; Division of Hematology, Medical University of Graz, 8010 Graz, Austria., Weichhart T; Center for Pathobiochemistry & Genetics, Medical University of Vienna, 1090 Vienna, Austria., Kratky D; Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.; BioTechMed-Graz, 8010 Graz, Austria. |
| Abstrakt: |
Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters and triglycerides at an acidic pH. In LAL deficiency (LAL-D), dysregulated expression of matrix metalloproteinase 12 (MMP-12) has been described. The overexpression of MMP-12 in myeloid lineage cells causes an immune cell dysfunction resembling that of Lal knockout ( Lal KO) mice. Both models develop progressive lymphocyte dysfunction and expansion of myeloid-derived suppressor (CD11b+ Gr-1+) cells. To study whether MMP-12 might be a detrimental contributor to the pathology of LAL-D, we have generated Lal/Mmp12 double knockout (DKO) mice. The phenotype of Lal/Mmp12 DKO mice closely resembled that of Lal KO mice, while the weight and morphology of the thymus were improved in Lal/Mmp12 DKO mice. Cytological examination of blood smears showed a mildly reversed lymphoid-to-myeloid shift in DKO mice. Despite significant decreases in CD11b+ Ly6G+ cells in the peripheral blood, bone marrow, and spleen of Lal/Mmp12 DKO mice, the hematopoietic bone marrow progenitor compartment and markers for neutrophil chemotaxis were unchanged. Since the overall severity of LAL-D remains unaffected by the deletion of Mmp12, we conclude that MMP-12 does not represent a viable target for treating the inflammatory pathology in LAL-D. |
