TLR10 is a Negative Regulator of Human Monocyte Innate Immune Responses

Abstract Toll-like receptors (TLRs) are important pattern recognition receptors involved in the activation of innate immune responses against foreign pathogens. Humans possess ten TLRs, of which TLR10 is the only remaining TLR without a known ligand, signaling pathway or cellular function. Recent data by our lab has shown for the first time a suppression of cellular innate immune responses in primary human monocytes that is mediated by a TLR10 monoclonal antibody. This study sought to expand on our initial observations by investigating the signaling pathways, gene expression and long-term consequences of TLR10 engagement on primary human monocytes. Our data shows that TLR10 engagement is sufficient to suppress both IL-6 and TNF-α induction in response to TLR4, TLR7/8 or CD40 stimulation. Cellular lysates show that the primary target of TLR10 signaling may be to inhibit phosphorylation of Akt and its downstream targets. To further this hypothesis, we have performed RNA sequencing on cellular extracts to determine which pathways are targeted by TLR10 signaling. Our data also suggests that these events also affect long-term differentiation of monocytes into macrophages and dendritic cells. Macrophages and dendritic cells differentiated in the presence of a TLR10 antibody exhibit suppressed differentiation markers such as CD80/CD86 and HLA-DR/CD16 respectively after four days of differentiation. These data show that TLR10 is a novel regulator of innate immune responses on primary human monocytes and may have eventual therapeutics benefits in chronic inflammatory and auto-immune diseases.