Innate extracellular mouse Hsp70 inflammatory properties are mediated by the interaction of Siglec-E and LOX-1 receptors.

Innate immune responses to cell damage-associated molecular patterns induce a controlled degree of inflammation, ideally avoiding the promotion of intense unwanted inflammatory adverse events. When released by damaged cells, Hsp70 can stimulate different responses that range from immune activation to immune suppression. The effects of Hsp70 are mediated through innate receptors expressed primarily by myeloid cells, such as dendritic cells (DCs). The regulatory innate receptors that bind to extracellular mouse Hsp70 (mHsp70) are not fully characterized, and neither are their potential interactions with activating innate receptors. Here, we show that extracellular mHsp70 interacts with a receptor complex formed by both inhibitory Siglec-E and activating lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) on DCs. We also find that this interaction takes place in lipid microdomains within the plasma membrane, and that Siglec-E acts as a negative regulator of LOX-1-mediated innate activation upon mHsp70 or oxidized LDL binding. Thus, Hsp70 can both bind to and modulate the interaction of inhibitory and activating innate receptors on the cell surface. These findings add another dimension of regulatory mechanism to indicate how self-molecules contribute to dampening of exacerbated inflammatory responses.