000012911 001__ 12911 000012911 005__ 20251007025650.0 000012911 02470 $$ahttps://doi.org/10.1073/pnas.2400413121$$2doi 000012911 037__ $$aTEXTUAL 000012911 037__ $$bArticle 000012911 041__ $$aeng 000012911 245__ $$aHigh-throughput screen identifies non inflammatory small molecule inducers of trained immunity 000012911 269__ $$a2024-07-08 000012911 336__ $$aArticle 000012911 520__ $$aTrained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation—a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training. 000012911 536__ $$oNational Science Foundation$$aGraduate Research Fellowship Program 000012911 536__ $$oNational Science Foundation$$cNSF 2140001 000012911 536__ $$oNational Institute of Allergy and Infectious Diseases$$cNIH 75N93019C00041$$aDiscovery of Adjuvant Program 000012911 536__ $$oDefense Threat Reduction Agency$$cHDTRA11810052 000012911 536__ $$oNational Institutes of Health$$cR01-GM134376 000012911 536__ $$oUniversity of Chicago$$qhttps://ror.org/024mw5h28$$rROR$$aDigestive Diseases Research Core Center 000012911 536__ $$oNational Institute of Diabetes and Digestive and Kidney Diseases$$cP30 DK042086 000012911 540__ $$a<p>© 2024 the Author(s)</p> <p>This article is distributed under <a href="https://creativecommons.org/licenses/by-nc-nd/4.0/" target="_blank">Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND)</a>.</p> 000012911 542__ $$fCC BY-NC-ND 000012911 594__ $$a<p>ATAC sequencing data have been deposited in GEO (<a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE270608">GSE270608</a>) (<a id="body-ref-r60-2" href="https://www.pnas.org/doi/10.1073/pnas.2400413121?ai=11ykq&amp;ui=hdp0&amp;af=T#core-r60" data-xml-rid="r60">60</a>).</p> 000012911 6531_ $$atrained immunity 000012911 6531_ $$ainnate immune memory 000012911 6531_ $$ainflammation 000012911 6531_ $$ametabolism 000012911 6531_ $$amacrophages 000012911 690__ $$aPritzker School of Molecular Engineering 000012911 690__ $$aThe College 000012911 691__ $$aBiological Sciences 000012911 7001_ $$1https://orcid.org/0000-0002-8903-9985$$2ORCID$$aKnight, Hannah Riley$$uUniversity of Chicago 000012911 7001_ $$1https://orcid.org/0000-0002-2153-2167$$2ORCID$$aKetter, Ellen$$uUniversity of Chicago 000012911 7001_ $$aUng, Trevor$$uUniversity of Chicago 000012911 7001_ $$1https://orcid.org/0000-0002-4972-1402$$2ORCID$$aWeiss, Adam$$uUniversity of Chicago 000012911 7001_ $$1https://orcid.org/0000-0002-8695-1637$$2ORCID$$aAjit, Jainu$$uUniversity of Chicago 000012911 7001_ $$aChen, Qing$$uUniversity of Chicago 000012911 7001_ $$aShen, Jingjing$$uUniversity of Chicago 000012911 7001_ $$aIp, Ka Man$$uUniversity of Chicago 000012911 7001_ $$1https://orcid.org/0009-0008-6983-0252$$2ORCID$$aChiang, Chun-yi$$uUniversity of Chicago 000012911 7001_ $$a Barreiro, Luis$$uUniversity of Chicago 000012911 7001_ $$1https://orcid.org/0000-0003-1273-0951$$2ORCID$$aEsser-Kahn, Aaron$$uUniversity of Chicago 000012911 773__ $$tPNAS 000012911 8564_ $$yArticle$$90c4c4002-3e3c-436f-9034-34b38fcf0a38$$s1372399$$uhttps://knowledge.uchicago.edu/record/12911/files/knight-et-al-2024-high-throughput-screen-identifies-non-inflammatory-small-molecule-inducers-of-trained-immunity.pdf$$ePublic 000012911 8564_ $$ySupporting information$$92edeb369-75b4-4cb3-9560-5ded00810568$$s20623097$$uhttps://knowledge.uchicago.edu/record/12911/files/pnas.2400413121.zip$$ePublic 000012911 908__ $$aI agree 000012911 909CO $$ooai:uchicago.tind.io:12911$$pGLOBAL_SET 000012911 983__ $$aArticle