Endothelial TLR2 promotes proangiogenic immune cell recruitment and tumor angiogenesis

Abstract

Toll-like receptor 2 contributes to innate immune responses in endothelial cells as well as in immune cells. A shared Toll for innate immunity Toll-like receptor 2 (TLR2) is found in various tissues but is best known for its role in the innate immune system of activating sentinel immune cells in response to infection. Using conditional knockout mice, McCoy et al. found that TLR2 also mediated innate immune signaling within the endothelium. TLR2 in endothelial cells activated proinflammatory signaling that promoted angiogenesis and immune cell recruitment in response to various “danger” signals, such as those produced during infection or tissue damage. Endothelial TLR2 also supported tumor growth in a mouse model of prostate cancer. These findings show that the endothelium contributes to innate immune responses and that TLR2 may be a therapeutic target in cancer (see also the Focus by Mahfoud and Petrova). Toll-like receptor 2 (TLR2) is implicated in various pathologies, mainly in terms of its function within innate immune cells. However, TLR2 is also present in endothelial cells. Here, we explored the physiological and pathophysiological roles of endothelial TLR2 signaling. We found that TLR2 was highly abundant in the endothelium within various tissues using TLR2-IRES-EGFP reporter mice and was required for proinflammatory endothelial cell function. Endothelial cells lacking TLR2 exhibited reduced proinflammatory potential at the protein, cell, and tissue levels. Loss of endothelial TLR2 blunted the inflammatory response to both exogenous and endogenous danger signals in endothelial cells in culture and in vivo. Endothelial TLR2 promoted tumor growth, angiogenesis, and protumorigenic immune cell recruitment in a mouse model of prostate cancer. Furthermore, the cell surface localization of P-selectin and the subsequent production of other critical cell adhesion molecules (such as E-selectin, ICAM-1, and VCAM-1) that recruit immune cells required endothelial TLR2. Our findings demonstrate that endothelial cells actively contribute to innate immune pathways and propose that endothelial TLR2 has a pathological role in proinflammatory conditions.