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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.<\/jats:p>","DOI":"10.3390\/ijms252011001","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T04:02:58Z","timestamp":1728878578000},"page":"11001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12"],"prefix":"10.3390","volume":"25","author":[{"given":"Martin","family":"Buerger","sequence":"first","affiliation":[{"name":"Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2799-5322","authenticated-orcid":false,"given":"Melina","family":"Amor","sequence":"additional","affiliation":[{"name":"Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Akhmetshina","sequence":"additional","affiliation":[{"name":"Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6823-7299","authenticated-orcid":false,"given":"Valentina","family":"Bianco","sequence":"additional","affiliation":[{"name":"Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria"},{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Perfler","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, 8010 Graz, Austria"},{"name":"Division of Hematology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4861-7021","authenticated-orcid":false,"given":"Armin","family":"Zebisch","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, 8010 Graz, Austria"},{"name":"Division of Hematology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-0797","authenticated-orcid":false,"given":"Thomas","family":"Weichhart","sequence":"additional","affiliation":[{"name":"Center for Pathobiochemistry & Genetics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1357-7573","authenticated-orcid":false,"given":"Dagmar","family":"Kratky","sequence":"additional","affiliation":[{"name":"Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria"},{"name":"BioTechMed-Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,13]]},"reference":[{"key":"ref_1","first-page":"115","article-title":"Inhibition of PPAR\u03b3 in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis","volume":"119","author":"Wu","year":"2012","journal-title":"Blood J. 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