Mmp12 Is Translationally Regulated in Macrophages during the Course of Inflammation

Author:

Kuntschar Silvia1,Cardamone Giulia1,Klann Kevin2,Bauer Rebekka1ORCID,Meyer Sofie Patrizia1,Raue Rebecca1,Rappl Peter1,Münch Christian23ORCID,Brüne Bernhard1345ORCID,Schmid Tobias14ORCID

Affiliation:

1. Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany

2. Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany

3. Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt, Germany

4. German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany

5. Fraunhofer Institute for Translational Medicine and Pharmacology, 60596 Frankfurt, Germany

Abstract

Despite the importance of rapid adaptive responses in the course of inflammation and the notion that post-transcriptional regulation plays an important role herein, relevant translational alterations, especially during the resolution phase, remain largely elusive. In the present study, we analyzed translational changes in inflammatory bone marrow-derived macrophages upon resolution-promoting efferocytosis. Total RNA-sequencing confirmed that apoptotic cell phagocytosis induced a pro-resolution signature in LPS/IFNγ-stimulated macrophages (Mϕ). While inflammation-dependent transcriptional changes were relatively small between efferocytic and non-efferocytic Mϕ; considerable differences were observed at the level of de novo synthesized proteins. Interestingly, translationally regulated targets in response to inflammatory stimuli were mostly downregulated, with only minimal impact of efferocytosis. Amongst these targets, pro-resolving matrix metallopeptidase 12 (Mmp12) was identified as a translationally repressed candidate during early inflammation that recovered during the resolution phase. Functionally, reduced MMP12 production enhanced matrix-dependent migration of Mϕ. Conclusively, translational control of MMP12 emerged as an efficient strategy to alter the migratory properties of Mϕ throughout the inflammatory response, enabling Mϕ migration within the early inflammatory phase while restricting migration during the resolution phase.

Funder

Deutsche Forschungsgemeinschaft

Open Access Publication Fund of Goethe University

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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