| Title: |
Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12. |
| Authors: |
Buerger, Martin1 (AUTHOR) martin.buerger@medunigraz.at, Amor, Melina1 (AUTHOR) melina.amor@medunigraz.at, Akhmetshina, Alena1 (AUTHOR) alena.akhmetshina@medunigraz.at, Bianco, Valentina1,2 (AUTHOR) valentina.bianco@medunigraz.at, Perfler, Bianca3,4 (AUTHOR) bianca.perfler@medunigraz.at, Zebisch, Armin3,4 (AUTHOR) armin.zebisch@medunigraz.at, Weichhart, Thomas5 (AUTHOR) thomas.weichhart@meduniwien.ac.at, Kratky, Dagmar1,6 (AUTHOR) dagmar.kratky@medunigraz.at |
| Source: |
International Journal of Molecular Sciences. Oct2024, Vol. 25 Issue 20, p11001. 13p. |
| Subject Terms: |
*MYELOID-derived suppressor cells, *LYSOSOMAL storage diseases, *MATRIX metalloproteinases, *MYELOID cells, *BONE marrow, *CHOLESTERYL ester transfer protein |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
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