Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14

• Published in: The EMBO journal Vol. 34; no. 22; pp. 2775 - 2788
• Main Authors: Fong, Jerry J, Sreedhara, Karthik, Deng, Liwen, Varki, Nissi M, Angata, Takashi, Liu, Qinglian, Nizet, Victor, Varki, Ajit
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 12-11-2015; Nature Publishing Group UK; John Wiley and Sons Inc
• Subjects: Antigens, CD - genetics; Antigens, CD - immunology; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - immunology; Cell Line, Tumor; Cellular biology; EMBO19; glycobiology; HEK293 Cells; Hsp70; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - immunology; Humans; Immune response; Immunology; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; innate immunity; Lectins - genetics; Lectins - immunology; Molecular biology; Monocytes - immunology; Monocytes - pathology; Polymorphism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Siglec; Signal Transduction - genetics; Signal Transduction - immunology; Hsp70; Siglec; innate immunity; glycobiology
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201591407

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.
Synopsis
Extracellular Hsp70 binds to the paired immunoreceptors Siglec‐5 and Siglec‐14 to elicit opposing immune responses. A polymorphism in human
SIGLEC14
modulates the effects of Hsp70 stimulation.
Extracellular Hsp70 engages the paired immunoreceptors Siglec‐5 and Siglec‐14.
Hsp70 sends opposing immunomodulatory signals through Siglec‐5 and Siglec‐14.
The human
SIGLEC14
polymorphism changes the effects of the Hsp70 stimulation.
These results may clarify previous contrasting studies on Hsp70 immunomodulation.
Graphical Abstract
Recognition of Hsp70 by different leukocyte receptors has either pro‐ or anti‐inflammatory effects, helping to reconcile previous contradictory findings on the extracellular role of this chaperone.