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Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / FRACHET Philippe

Altered-self phagocytosis: recognition and signaling

Participants

Pascale Tacnet-Delorme, Research Engineer CNRS, Ph.D.
Jean-Philippe Kleman*, Research Engineer CEA, Ph.D.
Philippe Frachet, Maître de conférences UGA, Ph.D.

Overview

Proper recognition and clearance of apoptotic cells is critical for many biological processes including development, tissue remodelling and maintenance of homeostasis. The rapid removal of unwanted self-cells by professional or non professional phagocytes prevents the release of their intracellular contents and is essential to reduce inappropriate inflammation and avoid autoimmune disorders. Nevertheless, apoptotic cell clearance has significant immunological impacts. Apoptotic cell recognition critically regulates immune responses, particularly when achieved by professional phagocytes such as macrophages or immature dendritic cells (DCs).
Our major objective is to shed light on the cascades of events that connect the recognition of apoptotic cells to the signaling that triggers the engulfment by professional scavengers, i.e. macrophages and dendritic cells. For this purpose, we will focus on the following aspects:
Recognition mechanisms: We aim at (i) identifying the « eat me » signals on apoptotic cell that are recognized by C1q and its phagocyte cell surface receptor(s), (ii) deciphering the role of C1q and its partners in the formation of the phagocytic synapse (i.e. C1q orientation, multi molecular complexes formation…). We focus more specifically on calreticulin-C1q interaction since calreticulin contributes to C1q-dependent uptake of apoptotic cells and because C1q and calreticulin could cooperate to modulate the phagocyte response and/or the macrophage maturation.

Intracellular signalling pathways that take place from the recognition of an apoptotic cell to its engulfment by a professional phagocyte e.g. the ELMO/DOCK pathway, essential for the actin cytoskeleton remodeling but also yet unknown process(es) triggering efficient “self” antigen presentation to immune cells.

Experimental strategies are developed at the cellular, biochemical and structural level. Technical approaches include cell culture, real time microscopy, flow cytometry, TAP-tag strategy, protein engineering and SPR analysis.

Collaborations

Tight Internal collaboration for structural and functional studies: Christine Gaboriaud, Dominique Housset and Nicole Thielens (IRPAS)
Pierre GANS (IBS NMR group).
Anne-Marie Di Guilmi (IBS Pneumoccocus group).
Statens Institute, Copenhagen, Denmark
Institut Cochin, Paris

Selected Publications

- Verneret, M., P. Tacnet-Delorme, R. Osman, R. Awad, A. Grichine, J.-P. Kleman, and P. Frachet. 2014. Relative contribution of c1q and apoptotic cell-surface calreticulin to macrophage phagocytosis. J Innate Immun 6: 426–434.
- Païdassi, H., P. Tacnet-Delorme, V. Garlatti, C. Darnault, B. Ghebrehiwet, C. Gaboriaud, G. J. Arlaud, and P. Frachet. 2008. C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J. Immunol. 180: 2329–2338.
- Païdassi, H., P. Tacnet-Delorme, M. Verneret, C. Gaboriaud, G. Houen, K. Duus, W. L. Ling, G. J. Arlaud, and P. Frachet. 2011. Investigations on the C1q-calreticulin-phosphatidylserine interactions yield new insights into apoptotic cell recognition. J. Mol. Biol. 408: 277–290.