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.

Hsc70 facilitates TGF-β-induced activation of Smad2/3 in fibroblastic NRK-49F cells

“…[16]. In immune cells, extracellular Hsp70 or Hsc70 stimulates a variety of immune regulatory pathways for cytokine production through receptors (e.g., Toll-like receptors 2, 4, CD40, CD91, CCR5, Siglec-5, 14, and members of scavenger receptors) [17,18]. We also reported that extracellular Hsc70 stimulates TNF-a production, and it was enhanced with specific peptides containing C-mannosyl Trp via the interaction with Hsc70 in macrophage-like RAW264.7 cells [19].…”

Heat Shock Proteins Promote Cancer: It's a Protection Racket

“…Extracellular HSPs can be proinflammatory in some contexts or show the opposite nature in others[91, 92]. When used as vaccines to chaperone tumor antigens, they can stimulate specific tumor immunity and lead to tumor regression[81].…”

Microbial recognition and danger signals in sepsis and trauma

“…Recent data has suggested that Hsp70 may indeed be an alarmin, but not signaling via TLR receptors, and perhaps, not simply as a proinflammatory agent. Rather, Hsp70 may be a ligand for siglec-5 and siglec-14 [87]. Siglecs are sialic acid binding immunoglobulin (Ig)-like lectins that are membrane attached receptors that bind sialic acid rich glycans.…”