Rheumatic Diseases Research Core
Stem Cell Center, Yale: Stem Cells and Tissue Repair
Inflammation involves a complex interplay of biochemical pathways that trigger and shape the immune response. These culminate in a coordinated response that is essential for protection against invading pathogens. Inflammation, if unchecked, can favor the development of chronic inflammatory and autoimmune diseases. Thus, mechanisms that regulate its duration and intensity are fundamental to immune homeostasis. Our research interest is to elucidate the mechanisms that underlie the regulation of inflammation and the homeostatic control of immune function. We have discovered a signaling pathway downstream of the TAM (Tyro3, Axl, Mer) receptor tyrosine kinases that limits the amplitude and phase of the inflammatory response. We are currently focusing on identifying the in vivo source of TAM ligands, unraveling the molecular determinants that account for the specificity of TAM-mediated inhibition, decoding the transcriptome activated during TAM-mediated inhibition of inflammation, and testing the role of TAM-mediated immune suppression in vivo. Our long-term goal is to manipulate this pathway as an innovative therapeutic strategy for the inhibition or enhancement of the inflammatory response.
Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells.
Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, Weinstein JS, Licona-Limon P, Schmid ET, Pelorosso F, Gagliani N, Craft JE, Flavell RA, Ghosh S, Rothlin CV. Science. May 11.
AXL receptor tyrosine kinase is required for T cell priming and antiviral immunitye.
Schmid ET, Pang IK, Carrera Silva EA, Bosurgi L, Miner JJ, Diamond MS, Iwasaki A, Rothlin CV. (2016)AXL receptor tyrosine kinase is required for T cell priming and antiviral immunityeLIFE Jun 28;5. pii: e12414. doi: 10.7554/eLife.12414.
The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity.
Chan PY, Carrera Silva EA, De Kouchkovsky D, Joannas LD, Hao L, Hu D, Huntsman S, Eng C, Licona-Limón P, Weinstein JS, Herbert DR, Craft JE, Flavell RA, Repetto S, Correale J, Burchard EG, Torgerson DG, Ghosh S, Rothlin CV. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352(6281):99-103. 2016
TAM Receptor Signaling in Immune Homeostasis.
Rothlin CV, Carrera-Silva EA, Bosurgi L, Ghosh S. TAM Receptor Signaling in Immune Homeostasis. Annu Rev Immunol. 2015 33:355-91
Tumor intrinsic EGFR and macrophage induced TNF-a signaling cooperate to promote GBM progression through aPKC.
Kusne Y, Carrera Silva E, Perry AS, Rushing EJ, Mandell EK, Dietrich J, Errasti A, Gibbs D, Berens ME, Loftus JC, Hulme C, Aldape K, Sanai N, Rothlin CV* and Ghosh S*. Tumor intrinsic EGFR and macrophage induced TNF-a signaling cooperate to promote GBM progression through aPKC. * co-corresponding authors. Science Signaling, 2014, 7(338), ra75.
Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer.
Bosurgi L, Bernink JH, Delgado Cuevas V, Gagliani N, Joannas L, Schmid ET, Booth CJ, Ghosh S and Rothlin CV. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13091-6
T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response.
Carrera Silva EA, Chan PY, Joannas L, Errasti AE, Gagliani N, Bosurgi L, Jabbour M, Perry A, Smith-Chakmakova F, Mucida D, Cheroutre H, Burstyn-Cohen T, Leighton JA, Lemke G, Ghosh S and Rothlin CV: T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response. Immunity. 2013 Jul 25;39 (1) :160-70. Epub 2013 Jul 11.
Immunobiology of the TAM receptors. Nat Rev Immunol.
Lemke G and Rothlin C.V. (2008). Immunobiology of the TAM receptors. Nat Rev Immunol 8(5): 327-336
TAM receptors are pleiotropic inhibitors of the innate immune response.
Rothlin C.V, Ghosh S., Zuniga E., Oldstone M.B., Lemke G.E (2007). TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131(6): 1124-1136.