Kodi Ravichandran Lab

Research focus

​Engulfment of apoptotic cells - the art of eating a good meal. Every day, we turn over billions of cells as part of normal development and homeostasis. The recognition and phagocytic removal of such cells destined to die (mostly via 'apoptosis') is fundamentally important for our health. Failure to promptly and efficiently clear apoptotic cells can lead to chronic inflammation, autoimmunity and developmental defects. The apoptotic cell clearance is usually done by neighboring cells or by professional phagocytes such as macrophages and dendritic cells. In studying this process, we consider four broad issues related to 'eating an apoptotic meal'. The first issue is getting to the meal itself. This involves the release of so called 'find-me signals' from apoptotic cells that serve as attraction cues to recruit monocytes and macrophages near an apoptotic cell. We have identified a critical for the nucleotides ATP and UTP as find-me signals that are released in a regulated way very early on during apoptosis (Elliott et al. Nature, 2009; Checkeni et al., Nature, 2010; Poon et al., Nature 2014).

The second issue is determining what is on the menu, and distinguishing the apoptotic cell from the neighboring healthy cells. This is achieved through expression of 'eat-me' signals on apoptotic cells and their recognition by receptors on phagocytes. Here, we focus on the ligands on the dying cell and receptors on phagocytes that are involved in the specific recognition of apoptotic cells. Our further work has identified a novel type of engulfment receptor (BAI1) that recognizes phosphatidylserine, a key eat-me signal exposed on apoptotic cells (Park et al. Nature 2007, Park et al. Current Biology, 2009; Hochreiter-Hufford et al., Nature 2013).

The third issue is the act of eating the meal itself. Here, we focus on the specific intracellular signals that are initiated within the phagocyte when it comes in contact with apoptotic cells, and how this leads to cytoskeletal rearrangements of the phagocyte and internalization of the target. We have defined the signaling pathway downstream of BAI1 involving the proteins ELMO1, Dock180 and the small GTPase Rac. We have also defined a second signaling module that involves the membrane protein LRP1 and a small intracellular adapter protein GULP. (Gumienny et al. Cell , 2001, Brugnera et al. Nature Cell Biology, 2002; Lu et al. Nature Str Mol. Biol. , 2004; deBakker et al. Currently Biology, 2004; Lu et al. Current Biology , 2005; Ravichandran, Cell, 2003).


Steps in apoptotic cell clearance: Recruitment, recognition, engulfment and processing. Our laboratory investigates all of these steps as well as the anti-inflammatory signaling associated with apoptotic corpse uptake, and how this differs from other forms of cell death.

 

We have also generated mice with knockout of specific engulfment genes and are currently characterizing them (Elliott et al., Nature, 2010). The fourth relates to 'after-the-meal' issues. Contrary to other types of phagocytosis (such as bacterial uptake), engulfment of apoptotic cells is 'immunologically silent' and is actively anti-inflammatory. We are interested in determining how apoptotic cells induce an anti-inflammatory state of the phagocyte, and how this relates to immune tolerance or suppression of inflammation (Juncadella et al., Nature, 2013, Mauldin et al., Current Biology, 2013). Another fun problem in considering one cell eating another is that the phagocyte essentially doubles its cellular contents (including protein, cholesterol, nucleotides etc.). We are addressing how the ingested cargo is processed within the phagocyte, and how the phagocyte manages homeostasis (Kinchen et al. Nature Cell Biology, 2008; Kiss et al. Current Biology, 2007; Ravichandran et al. Nature Rev Immunol. 2007; Kinchen et al, Nature 2010; Fond et al., J of Clinical Investigation, 2015), and what controls an appetite of the phagocyte in ingesting multiple apoptotic cells (Park et al., Nature, 2011). Recently, we have also become very interested in how phagocytes communicate with each other in a tissue (Han et al., Nature, 2016), and how one can boost cell clearance in vivo (Lee et al., Immunity, 2016). The overall goal of these studies is to understand the signaling pathways and the consequences of engulfment at the molecular, cellular, and whole organism levels. We use a combination of molecular biology, cell biology, biochemistry, coupled with C. elegans and mouse knockout studies, to gain insights on how specific proteins orchestrate the intracellular signaling during engulfment and lead to the immunologically silent clearance of apoptotic cells. These could have implications for future therapies aimed at limiting inflammation (Elliott et al., Journal of Cell Biol, 2010, Developmental Cell, 2016).
 

Movie of a phagocyte engulfing an apoptotic cell.  Here the phagocyte is unlabeled but the apoptotic cell is labeled with a dye Cypher5E that has low basal fluorescence but in the acidic pH of the lysosomes (within the phagocyte), fluoresces brighter. This provides a convenient way to track engulfed apoptotic cells.

Publications

Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammationHan C, Juncadella I, Kinchen J, Buckley M, Klibanov A, Dryden K, Onengut-Gumuscu S, Erdbrugger U, Turner S, Shim Y, Tung K, Ravichandran KNATURE, 539, 570-574, 2016
Unexpected link between an antibiotic, pannexin channels and apoptosisPoon I, Chiu Y, Armstrong A, Kinchen J, Juncadella I, Bayliss D, Ravichandran KNATURE, 507, 329-34, 2014
Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammationJuncadella I, Kadl A, Sharma A, Shim Y, Hochreiter-Hufford A, Borish L, Ravichandran KNATURE, 493, 547-51, 2013
Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosisChekeni F, Elliott M, Sandilos J, Walk S, Kinchen J, Lazarowski E, Armstrong A, Penuela S, Laird D, Salvesen G, Isakson B, Bayliss D, Ravichandran KNATURE, 467, 863-7, 2010
Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearanceElliott M, Chekeni F, Trampont P, Lazarowski E, Kadl A, Walk S, Park D, Woodson R, Ostankovich M, Sharma P, Lysiak j, Harden T, Leitinger N, Ravichandran KNATURE, 461, 282-6, 2009

Job openings

Kodi Ravichandran

Kodi Ravichandran

Research area(s)

Model organism(s)

Bio

PhD: Univ. of Massachusetts, Amherst, USA, 1992
Postdoc: Harvard Medical School, Boston, USA, 1992-96
Professor: Univ. of Virginia, Charlottesville, Virginia, USA, 1996-present
Director: Center for Cell Clearance, Univ. of Virginia, USA, 2008-present
Chair: Dept. of Microbiol., Immunol. & Cancer Biol., Univ. of Virginia, USA, 2010-present
Group leader at VIB since January 2017

Contact Info

VIB-UGent Center for Inflammation ResearchUGent-VIB Research Building FSVMTechnologiepark 927 9052 GENTRoute description