• 22140
1992 …2024

Research activity per year

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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. Majority of these cells die by via caspase-dependent apoptosis. The recognition and phagocytic removal of these apoptotic cells occurs via the process of ‘efferocytosis’ and is fundamentally important for our health. Failure to promptly and efficiently clear apoptotic cells can lead to chronic inflammation, autoimmunity and developmental defects. Efferocytosis is usually done by neighboring cells or by professional phagocytes such as macrophages and dendritic cells, although many non-professional phagocytes such as epithelial cells and fibroblasts can function as efferocytes in different tissues in vivo.

In studying efferocytosis, 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. Besides the phagocyte recruitment function, we have also identified a critical role for metabolites released from apoptotic cells as ‘good-bye signals’ that impact the tissue in multiple ways. In this context, we focus on Pannexin channels, which are ‘opened’ during apoptosis by caspase-mediated cleavage. Pannexins are one of the key conduits for release of metabolites from apoptotic cells. Pannexin channels can also play roles in live cells, for example in communication between Teff and Treg cells.

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 work has identified a novel role for the adhesion type GPCR BAI1 as a receptor for phosphatidylserine, a key eat-me signal exposed on apoptotic cells.  

The third issue we study 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 (imagine swallowing a neighbor nearly your own size!). We have extensively studied a signaling pathway downstream of BAI1 involving the proteins ELMO1, Dock180 and the small GTPase Rac in membrane reorganization. We have generated transgenic and knockout mice targeting various engulfment molecules. Our recent work has highlighted the induction of a solute carrier proteins (SLCs) program in phagocytes and how SLCs control the appetite of a phagocyte.  

The fourth topic relates to ‘after-the-meal’ issues. Contrary to other types of phagocytosis (such as bacterial uptake), engulfment of apoptotic cells 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.  

Another fun problem when one cell eats another cell is that the phagocyte essentially doubles its cellular contents (including protein, cholesterol, nucleotides etc. - think of a neighbor moving into your house!). We are addressing how the ingested cargo is processed within the phagocyte, and how the phagocyte manages homeostasis and continue to ingest multiple corpses in succession. Phagocytes do not function alone, and in tissues they are next to other phagocytes and other cells; thus, we also focus on how efferocytic phagocytes communicate with each other and other cells. Given how many auto-inflammatory diseases are now linked to failed or defective efferocytosis, we are interested in how we can boost efferocytosis in vivo. We study disease models of lung inflammation, arthritis, colitis, and atherosclerosis to pick apart the functional role efferocytosis and key regulatory players. The overall goal of these studies is to eventually benefit from manipulating the efferocytic process in disease states.

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  • Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release

    Tufan, T., Comertpay, G., Villani, A., Nelson, G. M., Terekhova, M., Kelley, S., Zakharov, P., Ellison, R. M., Shpynov, O., Raymond, M., Sun, J., Chen, Y., Bockelmann, E., Stremska, M., Peterson, L. W., Boeckaerts, L., Goldman, S. R., Etchegaray, J. I., Artyomov, M. N., Peri, F., & 1 othersRavichandran, K. S., Apr 11 2024, In: Nature. 628, 8007, p. 408-415 8 p.

    Research output: Contribution to journalArticlepeer-review

  • Targeting Efferocytosis in Inflammaging

    Poon, I. K. H. & Ravichandran, K. S., Jan 23 2024, In: Annual Review of Pharmacology and Toxicology. 64, p. 339-357 19 p.

    Research output: Contribution to journalReview articlepeer-review

    Open Access
    4 Scopus citations
  • Amount of Pannexin 1 in Smooth Muscle Cells Regulates Sympathetic Nerve-Induced Vasoconstriction

    Dunaway, L. S., Billaud, M., Macal, E., Good, M. E., Medina, C. B., Lorenz, U., Ravichandran, K., Koval, M. & Isakson, B. E., Feb 1 2023, In: Hypertension. 80, 2, p. 416-425 10 p.

    Research output: Contribution to journalArticlepeer-review

    Open Access
    1 Scopus citations
  • Apoptotic cell death in disease—Current understanding of the NCCD 2023

    Vitale, I., Pietrocola, F., Guilbaud, E., Aaronson, S. A., Abrams, J. M., Adam, D., Agostini, M., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., Aqeilan, R. I., Arama, E., Baehrecke, E. H., Balachandran, S., Bano, D., Barlev, N. A., Bartek, J., Bazan, N. G., & 208 othersBecker, C., Bernassola, F., Bertrand, M. J. M., Bianchi, M. E., Blagosklonny, M. V., Blander, J. M., Blandino, G., Blomgren, K., Borner, C., Bortner, C. D., Bove, P., Boya, P., Brenner, C., Broz, P., Brunner, T., Damgaard, R. B., Calin, G. A., Campanella, M., Candi, E., Carbone, M., Carmona-Gutierrez, D., Cecconi, F., Chan, F. K. M., Chen, G. Q., Chen, Q., Chen, Y. H., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Ciliberto, G., Conrad, M., Cubillos-Ruiz, J. R., Czabotar, P. E., D’Angiolella, V., Daugaard, M., Dawson, T. M., Dawson, V. L., De Maria, R., De Strooper, B., Debatin, K. M., Deberardinis, R. J., Degterev, A., Del Sal, G., Deshmukh, M., Di Virgilio, F., Diederich, M., Dixon, S. J., Dynlacht, B. D., El-Deiry, W. S., Elrod, J. W., Engeland, K., Fimia, G. M., Galassi, C., Ganini, C., Garcia-Saez, A. J., Garg, A. D., Garrido, C., Gavathiotis, E., Gerlic, M., Ghosh, S., Green, D. R., Greene, L. A., Gronemeyer, H., Häcker, G., Hajnóczky, G., Hardwick, J. M., Haupt, Y., He, S., Heery, D. M., Hengartner, M. O., Hetz, C., Hildeman, D. A., Ichijo, H., Inoue, S., Jäättelä, M., Janic, A., Joseph, B., Jost, P. J., Kanneganti, T. D., Karin, M., Kashkar, H., Kaufmann, T., Kelly, G. L., Kepp, O., Kimchi, A., Kitsis, R. N., Klionsky, D. J., Kluck, R., Krysko, D. V., Kulms, D., Kumar, S., Lavandero, S., Lavrik, I. N., Lemasters, J. J., Liccardi, G., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Luedde, T., MacFarlane, M., Madeo, F., Malorni, W., Manic, G., Mantovani, R., Marchi, S., Marine, J. C., Martin, S. J., Martinou, J. C., Mastroberardino, P. G., Medema, J. P., Mehlen, P., Meier, P., Melino, G., Melino, S., Miao, E. A., Moll, U. M., Muñoz-Pinedo, C., Murphy, D. J., Niklison-Chirou, M. V., Novelli, F., Núñez, G., Oberst, A., Ofengeim, D., Opferman, J. T., Oren, M., Pagano, M., Panaretakis, T., Pasparakis, M., Penninger, J. M., Pentimalli, F., Pereira, D. M., Pervaiz, S., Peter, M. E., Pinton, P., Porta, G., Prehn, J. H. M., Puthalakath, H., Rabinovich, G. A., Rajalingam, K., Ravichandran, K. S., Rehm, M., Ricci, J. E., Rizzuto, R., Robinson, N., Rodrigues, C. M. P., Rotblat, B., Rothlin, C. V., Rubinsztein, D. C., Rudel, T., Rufini, A., Ryan, K. M., Sarosiek, K. A., Sawa, A., Sayan, E., Schroder, K., Scorrano, L., Sesti, F., Shao, F., Shi, Y., Sica, G. S., Silke, J., Simon, H. U., Sistigu, A., Stephanou, A., Stockwell, B. R., Strapazzon, F., Strasser, A., Sun, L., Sun, E., Sun, Q., Szabadkai, G., Tait, S. W. G., Tang, D., Tavernarakis, N., Troy, C. M., Turk, B., Urbano, N., Vandenabeele, P., Vanden Berghe, T., Vander Heiden, M. G., Vanderluit, J. L., Verkhratsky, A., Villunger, A., von Karstedt, S., Voss, A. K., Vousden, K. H., Vucic, D., Vuri, D., Wagner, E. F., Walczak, H., Wallach, D., Wang, R., Wang, Y., Weber, A., Wood, W., Yamazaki, T., Yang, H. T., Zakeri, Z., Zawacka-Pankau, J. E., Zhang, L., Zhang, H., Zhivotovsky, B., Zhou, W., Piacentini, M., Kroemer, G. & Galluzzi, L., May 2023, In: Cell Death and Differentiation. 30, 5, p. 1097-1154 58 p.

    Research output: Contribution to journalReview articlepeer-review

    Open Access
    67 Scopus citations
  • Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation

    Van Hove, L., Toniolo, A., Ghiasloo, M., Lecomte, K., Boone, F., Ciers, M., Raaijmakers, K., Vandamme, N., Roels, J., Maschalidi, S., Ravichandran, K. S., Kasper, M., van Loo, G. & Hoste, E., 2023, In: Autophagy. 19, 11, p. 2958-2971 14 p.

    Research output: Contribution to journalArticlepeer-review

    Open Access