title: IL-33/ST2 axis promotes mast cell survival via BCLXL.
abstract: Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2(-/-) mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminth-infected intestine, and in normal peritoneum. To confirm an MC-intrinsic role for ST2 in vivo, we performed peritoneal transfer of WT and St2(-/-) MC. In St2(-/-) hosts treated with IL-33 and in WT hosts subjected to thioglycollate peritonitis, WT MC displayed a clear survival advantage over coengrafted St2(-/-) MC. IL-33 blockade specifically attenuated this survival advantage, confirming IL-33 as the relevant ST2 ligand mediating MC survival in vivo. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Jun-Xia
authors: JX
authors: Wang
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan;
authors: Shinjiro
authors: S
authors: Kaieda
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Sarah
authors: S
authors: Ameri
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Nadia
authors: N
authors: Fishgal
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Daniel
authors: D
authors: Dwyer
authors: Department of Nanoscience, Joint School of Nanoscience and Nanotechnology, University of North Carolina at Greensboro, Greensboro, NC 27412; and.
authors: Anthony
authors: A
authors: Dellinger
authors: Department of Nanoscience, Joint School of Nanoscience and Nanotechnology, University of North Carolina at Greensboro, Greensboro, NC 27412; and.
authors: Christopher L
authors: CL
authors: Kepley
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Michael F
authors: MF
authors: Gurish
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;Division of Immunology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 pnigrovic@partners.org.
authors: Peter A
authors: PA
authors: Nigrovic
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D006373:Helminthiasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000469:parasitology; D007596:Joints / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D051020:bcl-X Protein
keywords: arthritis; helminth infection