Günther Weindl

Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome A previously entirely unknown mode of TLR signal transduction is elucidated.

Beautiful work! Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome | Science Advances www.science.org/doi/10.1126/...

NLRP3 acts as a direct sensor of intracellular potassium ions https://www.biorxiv.org/content/10.64898/2026.03.12.707678v1

Most successful University of Excellence - In the atrium of the rectorate building, University members watched with bated breath as the decision on excellence was announced.

Most successful University of Excellence - Rector Hoch, together with the Rectorate and hundreds of guests, burst into cheers when the decision was announced.

Great news—We remain the most successful German University of Excellence! With eight Clusters of Excellence and funding secured until 2033, we’re moving closer to our goal of establishing our Uni permanently among the best universities in the world: www.uni-bonn.de/en/news/040-...
© VL/Uni Bonn

I am delighted to share our characterisation of natural antagonism of TLR7/8 in Nature Immunology. We propose a model where 2’O-Methyl RNA fragments keep TLR7/8 in check, preventing autoimmunity. > www.nature.com/articles/s41...

On the balance of knowledge Nature Reviews Immunology - Ruslan Medzhitov shares his thoughts on the balance between generating data and developing theories in immunology, with a focus on exploring the rules that govern...

In this World View article, Ruslan Medzhitov discusses the perils of too much data and not enough theory in modern immunology
rdcu.be/e2DCZ

Lipids challenge ligands to control receptors

The behaviour of a receptor protein can be influenced by the presence of certain lipids in the membrane it is embedded in.

🔗 buff.ly/G1Zl6cZ

Crosstalk between NLRP3 Signaling and Histone Deacetylases in Inflammasome-Driven Diseases The NLRP3 inflammasome is a validated therapeutic target in inflammatory, metabolic, and neurodegenerative diseases. Epigenetic regulators, particularly histone deacetylases (HDACs), have emerged as key modulators of inflammasome priming and activation. Recent advances in medicinal chemistry have provided new chemical modalities for the mechanistic interrogation and the potential therapeutic modulation of NLRP3 signaling. This Perspective dissects the mechanistic interface between HDAC-dependent epigenetic control and NLRP3 signaling and highlights emerging chemical tools, including isoform-selective inhibitors and targeted protein degraders. We discuss the challenges of isoform selectivity, species-specific differences, and the therapeutic potential of HDAC-based strategies to attenuate aberrant NLRP3 activity while minimizing off-target effects. Understanding this epigenetic-inflammasome crosstalk may provide a framework for translating epigenetic modulation into innovative treatments for inflammasome-driven diseases.

🚀 New Perspective in J Med Chem out now! #HDACs meet #NLRP3 #inflammasome 🔬 Many thanks for the great collaboration! #DrugDiscovery
pubs.acs.org/doi/10.1021/...

Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain–containing 3 (NLRP3) inflammasome hyperactivation and e...

Why is obesity often associated with dysregulated, low-grade chronic inflammation?
In our new paper in @science.org we show that obesity rewires nucleotide metabolism in immune cells, making inflammatory responses much easier to trigger. www.science.org/doi/10.1126/...

So excited that this study is now online! It's been a pleasure to work with BioAge Labs and our collaborators on this story. We characterise a new class of #NLRP3 inhibitors with translational potential for so many inflammatory diseases.

JCI - Biological and clinical implications of a model of surveillance immunity Advertisement

Very happy to share our favorite model for immune response initiation! @jclinical-invest.bsky.social @reisesousalab.bsky.social @lozanzi.bsky.social @caixaresearch.bsky.social @danieljdrucker.bsky.social @cp-immunity.bsky.social @cyrilpedia.bsky.social
www.jci.org/articles/vie...

Beyond excited to share our #NewPaper in @cellcellpress.bsky.social! Inflamed environments acidify intracellular #pH. BRD4 senses this via transcriptional condensates, tuning #macrophage responses to match demand and consequences of #inflammation authors.elsevier.com/sd/article/S...

Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly - Nature Communications NLRP3 inflammasome activation is critical for the induction of protective immunity, but molecular insights are still lacking. Here, the authors express NLRP3 variants targeted to different cellular lo...

Are there spatial restrictions in NLRP3 #inflammasome activation? I am super excited to share our new study spearheaded by amazing @elvirab.bsky.social
www.nature.com/articles/s41...

A collage with symbolic images of all eight clusters of excellence. A man working on a machine, an observatory, two people in a field, a woman writing something on a piece of paper, a woman in front of a device, a man writing something on a blackboard, an exhibition, a woman looking through a telescope.

A landmark success! The University of Bonn secured funding for all six existing Clusters of Excellence and both new initiatives – more than any other German university. More: www.uni-bonn.de/en/news/095-...

© G. Hübl, V. Lannert, M. Thürbach/ECONtribute, J. F. Saba/UKB, S. Wegener/ML4Q; N. Wietrich

This is figure 2, which shows single-cell characterization of the acute hyperinflammatory response to LPS administration.

A study in Nature Immunology uses a model of lipopolysaccharide injection in humans to characterize the transcriptomic landscape of bone marrow and blood immune cells during the hyperinflammatory and immunosuppressed phases of systemic inflammation. go.nature.com/44bj71Y

TLR4 endocytosis and endosomal TLR4 signaling are distinct and independent outcomes of TLR4 activation | EMBO reports imageimageContrary to the prevailing model, ligand-induced TLR4 endocytosis is not a prerequisite for endosomal TLR4 signaling in macrophages. TLR4 endocytosis requires the TIR domain, PLCγ2, SYK and ...

TLR4 endocytosis and endosomal TLR4 signaling are distinct and independent outcomes of TLR4 activation | EMBO reports www.embopress.org/doi/full/10....

What do Pablo Picasso and Charles Janeway have in common? Both were interested in patterns of life. Janeway was focused on pathogen associated molecular patterns (PAMPs) that are detected by our immune system. But what are these patterns he refers to?

#compchem
New work by Valerij Talagayev, Gerhard Wolber and me using tauRAMD to characterize unbinding paths of TLR8 agonist and antagonists. Interestingly, some ligands showed clear path preference:...
chemrxiv.org/engage/chemr...

Cell-autonomous innate immunity by proteasome-derived defence peptides Nature - Proteasomal degradation of cellular proteins generate defence peptides constitutively and in response to bacterial infection. Such peptides might provide a source of natural antibiotics...

rdcu.be/ecwJ9

The vasoconstrictor adenosine 5′-tetraphosphate is a danger signal that induces IL-1β - Molecular Medicine Background The endogenous nucleotide adenosine 5′-tetraphosphate (Ap4) is a potent vasoconstrictor. Despite its structural similarity to the danger signal adenosine 5’-triphosphate (ATP), the immunomo...

Our paper is out! Could the #nucleotide adenosine 5′-tetraphosphate (Ap4) promote #inflammation? Ap4 triggers IL-1β release distinct from canonical #inflammasome activators, shedding light on its potential role in #inflammaging. Kudos to Judith, Jonas, and collaborators! 👏 doi.org/10.1186/s100...

Discovery of Novel Isoxazole-Based Small-Molecule Toll-Like Receptor 8 Antagonists Toll-like receptor 8 (TLR8) recognizes viral and bacterial RNA, initiating inflammatory responses that are crucial for innate immunity. Dysregulated TLR8 signaling contributes to autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, driving chronic inflammation and tissue damage. Therefore, targeting TLR8 has gained attention as a promising therapeutic strategy. We report a novel selective TLR8 antagonist scaffold identified through computational modeling and simulation. In silico-guided rational drug design and synthesis led to potent isoxazole-based compounds that were characterized by structure–activity relationships. The most active compounds inhibited TLR8-mediated signaling in cell lines and primary cells, reduced MyD88 recruitment, suppressed NF-κB- and IRF-dependent signaling, and decreased inflammatory responses. In silico and pharmacological analyses demonstrated competitive binding to the pocket of chemical ligands within the TLR8 dimerization interface. These highly selective and potent TLR8 antagonists possess favorable physicochemical properties, representing potential clinical candidates for TLR8-targeted therapy.

🚀 Our latest paper is out in J Med Chem @acsmedi.bsky.social! 🔥 Huge kudos to first authors Troy & Valerij and the amazing teams of @gwolber.bsky.social & Matej Sova for this fantastic collaboration! 🙌 #DrugDiscovery #InnateImmunity #Autoimmune 🔗 pubs.acs.org/doi/full/10.1021/acs.jmedchem.4c03148

This is figure 1, which gives an overview of AI applications in the drug development pipeline.

A Review in Nature Medicine explores the state-of-the-art applications of artificial intelligence in small-molecule drug development, from target identification and drug synthesis up to clinical trial design and conduct. https://go.nature.com/4jFyuVG 🔒

www.cell.com/immunity/ful... - 👉ISD investigators now defined a mechanism whereby HDAC9 regulates activation of the NLRP3 inflammasome and developed a targeted anti-inflammatory approach for treating atherosclerosis. #HDAC9 #cell #immunity

A human metabolic map of pharmacological perturbations reveals drug modes of action - Nature Biotechnology Mapping the metabolic effects of drugs helps define their mode of action.

A human metabolic map of pharmacological perturbations reveals drug modes of action - @zampierilab.bsky.social @depbiomedicine.bsky.social go.nature.com/3CreANg

Our preprint on #NLRP3 #PROTACs has been published @chemcomm.bsky.social! Happy that we could contribute! pubs.rsc.org/en/content/a...

Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors. Here, we investigated the effects of the synthetic LPS-neutralizing peptide Pep19–2.5 on human P2X receptors in cells of the innate immune system. Pep19–2.5 concentration-dependently triggered Ca2+ influx, interleukin (IL)-1β, and lactate dehydrogenase (LDH) release in Toll-like receptor-stimulated human macrophages and monocytes. Ca2+ influx was mediated at least partially by P2X7 receptors, and IL-1β and LDH release by P2X7 receptors, respectively. Confocal microscopy confirmed the colocalization of Pep19–2.5 with P2X7 receptors. Pep19–2.5-induced IL-1β release in primed cells was dependent on K+ efflux, caspase-1, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasome. In the presence of the P2X7 receptor agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate, Pep19–2.5 reduced IL-1β and LDH release. In 1321N1, astrocytoma cells stably transfected with human P2X receptors, Pep19–2.5 potently modulated P2X7 and P2X4 receptors (IC50 values of 0.346 and 0.146 μM, respectively) but showed less (P2X1, P2X3) or no activity (P2X2) at other P2X receptor subtypes. Our findings underline the potential of LPS-neutralizing peptides as modulators of P2X receptors, thus expanding their applicability beyond the treatment of sepsis to the treatment of inflammatory diseases.

🔔 Happy to share our latest study showing that LPS-neutralizing #peptides fine-tune P2X receptor signaling to control #inflammation. 🔥 Kudos to first author Jonas and all collaborators! 👏 #pharmacology #inflammasome
pubs.acs.org/articlesonre...

Confronting risks of mirror life Broad discussion is needed to chart a path forward.

Mirror Bacteria: The biggest future threat to life on Earth. Leading scientists are raising the alarm before it becomes reality. Honored to play a small role in evaluating this work prior to publication.
www.science.org/doi/10.1126/...

Very happy to share our latest work just published in @jexpmed.bsky.social! #Firstpost

rupress.org/jem/article/...

Our amazing PhD student @lbernaleau.bsky.social shows that CCDC134 controls TLR biogenesis through the ER-chaperone Gp96. #ImmunoSky #innateimmunity #inflammation

Quick summary here:

SurfDock is a surface-informed diffusion generative model for reliable and accurate protein–ligand complex prediction - Nature Methods SurfDock is a method for predicting protein–ligand complex structures by leveraging multimodal protein information and generative diffusion frameworks. Its results can be generalized to unseen protein...

SurfDock: a surface-informed diffusion generative model for protein–ligand docking excels in accuracy, generalizability, and flexible ligand handling. It identified 7 novel ALDH1B1 inhibitors, showcasing its drug discovery potential.
nature.com/articles/s41...
Preprint: biorxiv.org/content/10.1...

The danger theory of immunity strikes back... rdcu.be/d1uQN

Tlr7 drives sex differences in age- and Alzheimer’s disease–related demyelination Alzheimer’s disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex ...

Tlr7 drives sex differences in age- and Alzheimer’s disease–related demyelination

www.science.org/doi/10.1126/...