Immune responses against antigens generally require an efficient activation of antigen-presenting cells (APCs). Currently, the targeting of vaccine antigens to APCs has emerged as a promising strategy for boosting vaccine immunogenicity. Here, we reported that the C-terminus of heat shock protein 60 (HSP6O-C) can activate mouse peritoneal macrophages to secret a series of cytokines, and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and NF-kappa B p65 was involved in the pathway. We showed that the activation effect of HSP6O-C on macrophages was independent of toll-like receptor (TLR) 4 and the TLR-associated myeloide differentiation factor 88 (MyD88). Knockdown of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) reduced the activation of HSP6O-C-induced macrophage p38 MAPK, NF-kappa B p65 and cytokine secretion to some extent. Finally, we found that HSP6O-C up-regulated the expression of LOX-1 on macrophages and ovalbumin (OVA) model antigen fused with HSP6O-C markedly enhanced OVA-specific IgG responses. Thus, our results unravel a novel LOX-1-dependent pathway by which HSP6O-C can effectively activate macrophages and APCs targeting based on LOX-1 interaction is a promising approach to improve vaccines. (C) 2018 Elsevier Inc. All rights reserved.