Abstract
Regulation of inflammation is necessary to balance sufficient pathogen clearance with excessive tissue damage. Central to regulating inflammation is the switch from a pro-inflammatory pathway to an anti-inflammatory pathway. Macrophages are well-positioned to initiate this switch, and as such are the target of multiple therapeutics. One such potential therapeutic is methylthioadenosine (MTA), which inhibits TNFα production following LPS stimulation. We found that MTA could block TNFα production by multiple TLR ligands. Further, it prevented surface expression of CD69 and CD86 and reduced NF-KB signaling. We then determined that the mechanism of this action by MTA is signaling through adenosine A2 receptors. A2 receptors and TLR receptors synergized to promote an anti-inflammatory phenotype, as MTA enhanced LPS tolerance. In contrast, IL-1β production and processing was not affected by MTA exposure. Taken together, these data demonstrate that MTA reprograms TLR activation pathways via adenosine receptors to promote resolution of inflammation.
Highlights
Inflammation is one of the first lines of defense against pathogens
Since MTA can inhibit LPS-induced TNFa production in RAW cells and in human PBMC [15,18,19], we asked whether MTA could inhibit TNFa production in mouse bone marrow derived macrophages (BMDM) in response to LPS and other Toll-like receptors (TLRs) ligands
We find that MTA blocks TNFa and IL-6 production and activation receptor expression through adenosine A2 receptors
Summary
Excessive or poorly regulated inflammation can itself lead to pathology. TLRs induce NFKB signaling, and there is a common set of inflammatory genes upregulated by multiple TLRs, including cytokines like TNFa [1]. TLR signaling is highly complex, one consequence of TLR ligation is activation of adaptor molecules such as Trif or MyD88, which in turn leads to the activation of IRAK4, TRAF6, IRAK1 and other molecules [1]. This activation cascade culminates in propagation of signals to the nucleus, including via NF-KB [1]
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