Different Tlr Agonists Tend to Elicit an Immune- Regulatory Cytokine and Chemokine Phenotype in Human Microglia Submitted for Publication

Microglia, the macrophage-like cells in the CNS, express different TLRs that recognize conserved microbial structures and endogenous danger signals. Preliminary studies have indicated that human microglia cells express a wide range of different TLR family members as opposed to astrocytes and oligodendrocytes which primarily express TLR2, TLR3 and TLR4. Here, we show that cultured human microglia consistently express all TLR family members at readily detectable levels, with relatively high levels of TLR1, TLR2, TLR3 and TLR4. Levels of individual TLRs are differentially modulated by cytokines and TLR agonists themselves. In order to shed more light on the impact of TLR activation, we examined the response of human microglia to agonists for TLR3, 4, 7/8 or 9 by evaluating the induction of 40 different cytokines and chemokines. Cultured microglia in the absence of TLR agonists are already activated to some extent, and secrete marked amounts of various chemokines. In the presence of different TLR agonists, a strikingly similar cytokine and chemokine response profile was observed. In most cases, enhanced production was observed of the cytokines IL-13, IL-10, IL-11, IL-12p40, TGF-β, TNF-α and IL-1β and of the chemokines, CCL1, CCL5, CXCL10 and CCL15. Very limited, if any, induction of IL-12 was observed. Interestingly, this response profile is exemplary for an immune-regulatory macrophage phenotype rather that being representative for classically or alternatively activated macrophages. Our findings therefore suggest that human microglia tend to mount an immune-regulatory response to different TLR agonists.