Regulation of human macrophage metabolism by Toll-like receptors

• Applicant: Dr. Mario Lauterbach
• Subject Area: Immunology ; Biochemistry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506166706

Macrophages are cells of the innate immune system that populate tissues of the body, where they contribute to immunosurveilance. Amongst others they express Toll-like receptors (TLRs), a class of receptors that recognizes microbial products and once activated cause macrophages to mount an inflammatory response. These processes are tightly regulated as insufficient TLR activation leads to increased susceptibility to infections, whereas overshooting inflammation may lead to tissue damage and autoimmunity. Many studies have shown in great detail that upon activation of TLR4 by bacterial lipopolysaccharide macrophages adopt their metabolism to enhance their inflammatory capacities. Much less is known on how other members of the TLR family affect macrophage metabolism. We could show that downstream of TLR4 activation macrophages increased glucose metabolism to synthesize Acetyl-CoA the substrate for histone acetyltransferases. As a result histone acetylation was enhanced facilitating proinflammatory gene induction. We found that the metabolic changes observed early after stimulation required signaling through the adapter proteins MyD88 and TRIF. As all other members of the TLR family also require either of the two adapters for signal transduction our results suggest that they also may affect cellular metabolism once activated. With this research proposal we aim to investigate how other members of the TLR family change macrophage metabolism to boost their inflammatory response. Using mass spectrometry base metabolomics and stable isotope assisted flux analysis we aim to comprehensively analyze metabolism of primary human macrophages after stimulation with different TLR ligands. We specifically are interested in changes in central carbon metabolism and metabolism of acetyl-CoA, but we will also perform global untargeted analyses to systematically characterize similarities and distinctions between different TLR stimulations. We also aim to investigate the role of MyD88, TRIF and the Interferon-β receptor in shaping macrophage metabolism downstream of TLR activation. Given the different nature of microbes that sensed by the different TLR family members, we hypothesize that different TLR stimuli elicit distinct metabolic responses that are suited to support the metabolic needs of macrophages in the context of a given infection. Identifying such in will help to understand how human macrophages integrate their metabolism into their inflammatory response and may open therapeutic opportunities in the context of inflammatory diseases or vaccine adjuvant development.

• DFG Programme: Research Grants