Involvement of cell surface 90 kDa heat shock protein (HSP90) in pattern recognition by human monocyte-derived macrophages

Abstract

Heat shock proteins (HSPs) are typical intracellular chaperones which also appear on the cell surface and in extracellular milieu. HSP90, which chaperones many proteins involved in signal transduction, is also a regular component of LPS-signaling complexes on Mϕ. As LPS is a prototypical PAMP, we speculated that HSP90 is engaged in pattern recognition by professional phagocytes. In this report, we provide the first evidence, to our knowledge, of the geldanamycin (Ge)-inhibitable HSP90 on the surface of live monocyte-derived Mϕs (hMDMs). Using cytometry and specific Abs, we showed both HSP90 isoforms (α and β) on the surface of human monocytes and hMDMs. The cell-surface HSP90 pool was also labeled with cell-impermeable Ge derivatives. Confocal analysis of hMDMs revealed that HSP90-inhibitor complexes were rapidly clustered on the cell surface and recycled through the endosomal compartment. This finding suggests that the N-terminal (ATPase) domain of HSP90 is exposed and accessible from the extracellular space. To study the role of cell-surface HSP90 in pattern recognition, we used pathogen (PAMPs)- or apoptotic cell-associated molecular patterns (ACAMPs). We showed that blocking the cell-surface HSP90 pool leads to a dramatic decrease in TNF production by monocytes and hMDMs exposed to soluble (TLRs-specific ligands) and particulate [bacteria (SA) and (PG)] PAMPs. Surprisingly, in hMDMs the functional cell-surface HSP90 was not necessary for the engulfment of either apoptotic neutrophils or bacteria. The presented data suggest that the cell-surface HSP90 is a "signaling complex chaperone," with activity that is essential for cytokine response but not for target engulfment by Mϕ.

Exposure of Monocytic Cells to Lipopolysaccharide Induces Coordinated Endotoxin Tolerance, Mitochondrial Biogenesis, Mitophagy, and Antioxidant Defenses

“…In one study, following exposure to LPS, the sequential activation of SIRT1 and SIRT3 was found to integrate the induction of mitochondrial biogenesis with the down-regulation of pro-inflammatory responses ( 36 ). Another potential link between immunity and mitochondrial homeostasis is suggested by findings that the intracellular chaperone heat shock protein-90 (HSP90) is both essential for effective clearance of defective mitochondria by mitophagy and implicated, through accumulation at the cell surface, in the suppression of TNFα production in response to LPS ( 70 , 71 ).…”

Diversity and environmental adaptation of phagocytic cell metabolism

“…There are presumably many undiscovered fuels and signals associated with tumors involved in metabolic alterations and polarization in macrophages. Other mechanisms by which tumor‐associated macrophage differentiation may be facilitated are highlighted by the caspase‐dependent cleavage of peroxisome PPAR‐γ, which results in the inhibition of fatty acid oxidation and accumulation of tumor associated macrophage (TAM)‐promoting lipid droplets Another intriguing mechanism by which tumors may influence phagocyte metabolism is by alterations in expression or function by cell surface proteins, such as HSP90 . Although HSP90 is a typical cytoplasmic/nuclear chaperone protein capable of regulating mitophogy and cytokine production in macrophages, it also comprises a pool of cell surface associated proteins potentially regulated by extracellular cues such as tumors.…”

Substance P Improves Renal Ischemia Reperfusion Injury Through Modulating Immune Response

“…In addition, repression of pro-inflammatory cytokine from macrophage reduced the damage of AKI (43). For example, heat shock protein (HSP) 90 is associated with pro-inflammatory cytokine production of monocyte and macrophage and its inhibition reduced the damage of AKI (44,45). Macrophages have two distinct phenotypes and functions, and their polarization is regulated by the surrounding microenvironment (46,47).…”