title: Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14.
abstract: The intracellular chaperone heat-shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig-superfamily lectins on mammalian leukocytes that recognize sialic acid-bearing glycans and thereby modulate immune responses. Siglec-5 and Siglec-14, expressed on monocytes and neutrophils, share identical ligand-binding domains but have opposing signaling functions. Based on phylogenetic analyses of these receptors, we predicted that endogenous sialic acid-independent ligands should exist. An unbiased screen revealed Hsp70 as a ligand for Siglec-5 and Siglec-14. Hsp70 stimulation through Siglec-5 delivers an anti-inflammatory signal, while stimulation through Siglec-14 is pro-inflammatory. The functional consequences of this interaction are also addressed in relation to a SIGLEC14 polymorphism found in humans. Our results demonstrate that an endogenous non-sialic acid-bearing molecule can be either a danger-associated or self-associated signal through paired Siglecs, and may explain seemingly contradictory prior reports on extracellular Hsp70 action.
authors.affiliation: Glycobiology Research and Training Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Cellular and Molecular Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA.
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Fong
authors.affiliation: Glycobiology Research and Training Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Cellular and Molecular Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Sreedhara
authors.affiliation: Glycobiology Research and Training Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Pathology, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA.
authors.forename: Liwen
authors.initials: L
authors.lastname: Deng
authors.affiliation: Glycobiology Research and Training Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Pathology, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA.
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Qinglian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Glycobiology Research and Training Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Pediatrics, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA UC San Diego School of Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA vnizet@ucsd.edu a1varki@ucsd.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Glycobiology Research and Training Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Cellular and Molecular Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA Department of Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA UC San Diego School of Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA vnizet@ucsd.edu a1varki@ucsd.edu.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D037102:Lectins / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018840:HSP70 Heat-Shock Proteins; D037102:Lectins; D011956:Receptors, Cell Surface; C514213:SIGLEC14 protein, human; C114531:SIGLEC5 protein, human
keywords: Hsp70; Siglec; glycobiology; innate immunity