Met-signaling Controls Dendritic Cell Migration by Regulating Podosome Formation and Function

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Signaling by the HGF receptor/Met in skin-resident Langerhans cells (LC) and dermal dendritic cells (dDC) is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. Here we addressed the role of Met-signaling in distinct steps of LC/dDC emigration from skin by employing a conditional Met-deficient mouse model (Metf lox/flox ). We found that Met deficiency severely impaired podosome formation in DC and concomitantly decreased proteolytic degradation of gelatin. Accordingly, Met-deficient LC failed to efficiently cross the extracellular matrix (ECM) rich basement membrane between epidermis and dermis. We further observed that Met-signaling by HGF reduced adhesion of bone marrow-derived LC to various ECM factors and enhanced the motility of Met-signaling competent DC in a 3D collagen matrix, which was not the case for Met-deficient LC/DC. We found no impact of Met-signaling on the integrin-independent amoeboid migration of DC in response to the CCR7 chemokine CCL19. Collectively, our data show that the Met-signaling pathway regulates the migratory properties of DC in HGF-dependent and HGF-independent manners.

Authors 5

1. Ahmed E.I. Hamouda Aachen Institute for Biomedical Engineering Department of Cell Biology

   RWTH Aachen University

   Affiliation as printed

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany

   Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 0, 5074 Aachen, Germany

2. Carmen Schalla Aachen Institute for Biomedical Engineering Department of Cell Biology

   RWTH Aachen University

   Affiliation as printed

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany

   Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 0, 5074 Aachen, Germany

3. Antonio S. Sechi Aachen Institute for Biomedical Engineering Department of Cell Biology

   RWTH Aachen University

   Affiliation as printed

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany

   Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 0, 5074 Aachen, Germany

4. Martin Zenke Aachen Institute for Biomedical Engineering Department of Cell Biology

   RWTH Aachen University

   Affiliation as printed

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany

   Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 0, 5074 Aachen, Germany

5. Thomas Hieronymus corresponding Aachen Institute for Biomedical Engineering Department of Cell Biology

   RWTH Aachen University

   Affiliation as printed

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany

   Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany

   Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 0, 5074 Aachen, Germany