Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

Abstract

Circulating heat shock protein (HSP)‐27 is associated with tumor progression and increased post‐injury infection. Extracellular HSP‐27 might alter monocyte (MO)‐derived DC and/or MΦ function to mediate immunosuppression. HSP‐27 treatment inhibited expression of CD1a and CD1b/c, antigen uptake, and allogeneic T cell induction (MLR) by IL‐4 + GM‐CSF‐differentiated human DC while increasing some MΦ characteristics (↑CD14, ↑CD16, ↑CD163). MO cytokine receptor profiles elicited by 24‐h exogenous HSP‐27 treatment remained supportive of immature DC (iDC) emergence (↑IL‐4R, ↓IL‐6R, ↓M‐CSFR). IL‐10, IL‐6, and M‐CSF (which promote MΦ differentiation) were significantly increased in IL‐4 + GM‐CSF + HSP‐27 MO→iDC differentiation cultures. However, HSP‐27 treatment during MO differentiation to DC increased programmed cell death ligand 1 coinhibitor and depressed CD86 costimulator expression in parallel to decreased iDC MLR activity. This suggested that increased MΦ differentiation was not solely responsible for HSP‐27 reduction of differentiating DC activity. HSP‐27 treatment actually depressed the phagocytic capacity of MO differentiated to MΦ by IL‐10 or M‐CSF culture. CD163 (hemoglobin receptor) expression was depressed on M‐CSF + HSP‐27 MO‐derived MΦ. HSP‐27‐mediated inhibition of MO→iDC differentiation was reversed by p38α & β inhibitor (SB202190) addition or TLR4 receptor modulation. HSP‐27 impaired appropriate MO→iDC and MO→MΦ differentiation modulating expression of receptors necessary for their proper functions. This suggests that endogenous HSP‐27 has immunoregulatory activities which could contribute to immunopathology.

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

“…The first evidence for this was the finding that the addition of exogenous Hsp27 to human monocytes resulted in a high IL-10 to low TNF-α ratio similar to that described for BiP (De et al 2000). It has been further shown that Hsp27 inhibits the differentiation of monocytes into macrophages and of monocytes into immature dendritic cells by both IL-10-dependent and IL-10-independent pathways (Laudanski et al 2007). One emerging concept in immunology is that the immune system is more concerned with signals that cause damage than it is with self/non-self (Matzinger 2002).…”

Extracellular HSP110 skews macrophage polarization in colorectal cancer

“…In particular, we have previously shown that HSP70, expressed at the surface of tumor-derived exosomes, activated myeloid-derived suppressive cells through its binding to TLR2. 19 Concerning circulating HSP27, we and others have shown that it inhibits macrophage and dendritic cell differentiation through TLR4 21 and it favors angiogenesis through TLR3. 36 We show here that the antiinflammatory effect of soluble HSP110 on macrophages involves TLR4.…”

“…In this way, recombinant HSP27 has been shown to directly inhibit dendritic cell differentiation and skew toward a macrophage phenotype. 21 Furthermore, these macrophages acquire tolerogenic properties in vitro and in breast cancer patients. 20 Similar immunosuppression was observed in higher molecular weight HSPs, like recombinant HSP70, as Ferat-Osio et al showed that highly purified HSP70 inhibits TNFa production by monocytes.…”

A Paradoxical Role for Myeloid-Derived Suppressor Cells in Sepsis and Trauma

“…Another circulating mediator, heat shock protein (HSP) 27, is associated with tumor progression and increased post-injury infection. Laudanski et al have reported that elevated levels of HSP27 blocked the differentiation of myeloid precursors to dendritic cells and macrophages through a p38 MAP kinase-dependent pathway (47). These findings suggest that there are a number of inflammatory mediators that regulate the maturation of MDSCs, suggesting that therapeutic interventions may be possible but challenging.…”