LPS Regulation of Macrophage Function

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DESCRIPTION (provided by applicant): Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way they must be able to tailor their response to specific pathogens. These cells have evolved pattern recognition receptors (PRRs) that recognize conserved molecular patterns characteristic of the microbe which are not found within the host. Recognition of the specific combination of patterns by the PRRs allows the host cell to phenotype the invader and to respond appropriately. The Toll-like receptors, or TLRs, are the prototypic pattern recognition receptors. TLR activation is critical for host defense; however, if it is not tightly regulated inflammatory disease ensues. While much is known about the signaling pathways that are activated by TLRs, little is known about the inhibitory mechanisms that attenuate the inflammatory response. We have found that a transcription factor, ATF3, that is induced by LPS in macrophages is a potent attenuator of TLR4-induced transcription of IL-6, IL-12, and TNF. Consistent with this, ATF3 null mice are highly susceptible to LPS-induced shock and to infection with Salmonella. We propose to define the mechanism by which ATF3 attenuates TLR-signaling. A. We will first define the role of ATF3 posttranslational modifications in the regulation of ATF3/HDAC1 interactions, chromatin remodeling, and transcriptional control. B. We will delineate the mechanism by which ATF3 interacts with NF-?B, and C/EBP? to coordinate the transcription of cytokine genes. C. We will examine the role of ATF3 in innate immunity in mice. Lay summary. The proteins that are being investigated have a pivotal role in regulating the inflammatory and immune response in people. They instruct the body to effectively combat infectious disease, and an understanding of their function will permit us to make better vaccines. However, these molecules are a two-edged sword. When they function incorrectly they lead to inflammatory and autoimmune diseases. Understanding how this happens will lead to the design and production of better drugs for diseases such as rheumatoid arthritis.