bims-cediti 2026-05-31 papers

Issue of 2026–05–31
six papers selected by
Kateryna Shkarina, Universität Bonn

Nat Commun. 2026 May 30.

Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation.

María Mateo-Tórtola, Inga V Hochheiser, Gaopeng Li, Lukas Funk, Atousa Hashemi, Xiao Liu, Jane Torp, Lena Erlebach, András Szolek, Jelena Grga, Francesca Bork, Jana S Müller, Deborah Kronenberg-Versteeg, Matthias Geyer, Alexander N R Weber, Ana Tapia-Abellán.

The NLRP3 inflammasome contributes to a wide range of conditions from infections to Alzheimer's disease. NLRP3 forms an inactive decameric cage, that upon interaction with the trans-Golgi network (TGN) and microtubule organization center (MTOC), leads to inflammasome activation, yet whether non-decamer NLRP3 species form functional inflammasomes remains unclear. Here, we design a NLRP3 exon 3 deletion variant that forms low molecular weight NLRP3 assemblies. Spatially and dynamically highly resolved microscopy in THP-1 and human macrophages shows that nigericin, a K+-dependent NLRP3 stimulus, can trigger two distinct activation pathways: (i) the rapidly engaged decameric cage-dependent pathway; and (ii) a decameric cage-independent, TGN/MTOC-distal, and slow-reacting pathway employed by low molecular weight NLRP3 species, that dominates in human neutrophils. Collectively, our results delineate two parallel yet biologically distinct NLRP3 activation pathways, thereby providing a framework to understand NLRP3-driven inflammation across a wide range of pathological context and cell types.

DOI: https://doi.org/10.1038/s41467-026-72627-x

Sci Adv. 2026 May 29. 12(22): eaeb2368

Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis.

Marian Brenner, Sina Höhlein, Paul Wirth, Leon Neidt, Melina Lappe, Elisa Hopke, Eirini Sfakianaki, Martina Fischer, Kerstin Hadamek, Angelika Keller, Sebastian Bothe, José Pedro Friedmann Angeli, Anna M Schmoker, Arminja N Kettenbach, Agnes Fekete, Werner Schmitz, Ingrid Tessmer, Elisabeth Jeanclos, Antje Gohla.

Modulating ferroptosis, a form of cell death driven by uncontrolled lipid peroxidation, is of interest in numerous diseases. Here, we found that the deletion of phosphoglycolate phosphatase (PGP), an essential enzyme that safeguards high glycolytic flux, suppresses ferroptosis. Using metabolomic and isotopic labeling experiments together with lipid and proteomic profiling, we find that PGP loss drives a rewiring of the pentose phosphate pathway and of cellular energy and lipid metabolism that triggers a multifactorial antioxidant response. Paradoxically, our attempts to block PGP pharmacologically led to the realization that the recently described PGP inhibitor compound 1 (CP1) exerts a strong ferroptosis-sensitizing effect. Using genetic, biochemical, and biophysical approaches, we characterize CP1 as a direct, species-independent, dual inhibitor of PGP and ferroptosis suppressor protein 1 (FSP1), and further find that CP1 triggers FSP1 self-assembly. In sum, we identify PGP as a target protein for ferroptosis control and introduce a small-molecule FSP1 inhibitor with unique features to the armamentarium of pharmacological ferroptosis modulators.

DOI: https://doi.org/10.1126/sciadv.aeb2368

Sci Adv. 2026 May 29. 12(22): eaef5520

DHX36 is a regulatory switch in the interferon-mediated antiviral response.

Lisa Weixler, Daniel Hilbig, Philipp S Simon, Stefan Juranek, Julia Mahlberg, Martin Schlee, Eva Bartok, Markus Hafner, Katrin Paeschke.

Innate immune and stress responses must be tightly regulated to prevent aberrant activation in the absence of pathogens. The RNA helicase DHX36 has been implicated in viral RNA sensing, but its role in immune regulation is not fully understood. Here, we show that DHX36 functions as a rheostat that restrains immune activation under homeostatic conditions while modulating antiviral signaling. Exposure to double-stranded RNA reduces DHX36 activity, enabling immune activation. In contrast, cells lacking DHX36 adopt a constitutively activated immune state characterized by accumulation of RNA G-quadruplex structures, protein kinase R (PKR)-dependent stress granule formation, and elevated interferon-stimulated gene expression. These cells also display enhanced responsiveness to the viral RNA sensor retinoic acid-inducible gene I (RIG-I) and more effectively suppress replication of a yellow fever virus replicon. Together, our findings position DHX36 as a key regulator of the type I interferon response, linking RNA structure surveillance to coordinated PKR- and RIG-I-dependent antiviral signaling and maintenance of immune homeostasis.

DOI: https://doi.org/10.1126/sciadv.aef5520

Immunohorizons. 2026 May 13. pii: vlag023. [Epub ahead of print]10(5):

RANKL inhibits macrophage proinflammatory Toll-like receptor 2 and 4 signaling and impairs killing of intracellular bacteria.

Clara D Si, Christopher T Peek, Sana R Fatah, Andrew J Beaudoin, Anton R Zhelonkin, Kara R Eichelberger, Stacy L Hahn, Robert O Watson, Denis A Mogilenko, James E Cassat.

Monocyte-macrophage lineage cells, crucial components of the innate immune system, can uniquely form bone-resorbing osteoclasts upon exposure to the cytokine receptor activator of nuclear factor κB ligand (RANKL) in the bone microenvironment. Recent studies have also begun to uncover extensive extraskeletal roles of RANKL. However, how monocyte-macrophage lineage cells respond to RANKL outside of the bone, and the impact that this signaling pathway exerts on the host immune response, is not fully understood. In this study, we sought to define how RANKL exposure shapes the macrophage inflammatory response to pathogens by using the model intracellular bacterium Salmonella enterica serovar Typhimurium, which coopts macrophages to cause life-threatening infections. We found that exposing both mouse and human macrophages to subosteoclastogenic levels of RANKL increased intracellular Salmonella enterica serovar Typhimurium burdens and decreased proinflammatory cytokine production. RNA sequencing revealed downregulation of pattern recognition receptor signaling pathways in RANKL-treated macrophages during the early stages of infection. Therefore, we hypothesized that RANKL impairs pattern recognition receptor-dependent signaling pathways that are important for proinflammatory cytokine production. We discovered that RANKL-treated macrophages exhibit reduced nuclear factor κB and interferon regulatory factor 3 activation, specifically in response to Toll-like receptor 2 (TLR2) and TLR4 stimulation. We determined that prior RANKL exposure decreases abundance of the TLR2 and TLR4 adaptor proteins TRAM (TRIF-related adaptor molecule) and TIRAP (TIR domain-containing adaptor protein). Together, these data suggest that RANKL exposure negatively impacts the macrophage TLR-mediated inflammatory response to bacteria.

Keywords: Salmonella Typhimurium; RANKL; TLR signaling; innate immunity; macrophages

DOI: https://doi.org/10.1093/immhor/vlag023

Cell Death Dis. 2026 May 30.

NLRP1 inflammasome activation in skin equivalents reveals mechanistic insights into the roles of keratinocytes in psoriasis.

Michela Di Filippo, Tugay Karakaya, Marta Slaufova, Phil F Cheng, Paulina Hennig, Petra Boukamp, Steve Pascolo, Julia-Tatjana Maul, Isabel Kolm, Mitchell P Levesque, Thomas Kündig, Hans-Dietmar Beer.

The pro-inflammatory cytokines interleukin(IL)-1β and IL-36γ are key drivers of psoriasis, an inflammatory skin disease for which a causal therapy is not available. However, the mechanisms underlying regulation of these cytokines in psoriasis remain poorly understood. Generation of IL-1β activity is regulated by inflammasomes. We activated the NLRP1 inflammasome in human keratinocytes cultivated in three-dimensional skin equivalents. NLRP1 activation induced histological and molecular features highly reminiscent of psoriasis. Mechanistically, the phenotype was dependent on IL-1, which triggered a pro-inflammatory epidermal-dermal crosstalk. This included induction of IL-36γ expression, which was released from keratinocytes through NLRP1 inflammasome-induced gasdermin D pores. The relevance of these findings is reflected by the expression of NLRP1 and inflammasome activation in lesions of psoriasis patients. Finally, we discovered endogenous cytoplasmic double stranded (ds) RNA, recently associated with cellular perturbations in psoriasis, as a novel NLRP1 activator. Our results identify a novel endogenous dsRNA-mediated NLRP1-IL-1-IL-36γ signaling axis relevant in psoriasis and suggest its targeting as a promising treatment strategy.

DOI: https://doi.org/10.1038/s41419-026-08908-6

Cell Commun Signal. 2026 May 28.

Neutrophil extracellular traps promote macrophage activation through Toll-like receptor engagement and PKA and NF-kB signaling pathways.

Barbara Simonson Gonçalves, Jairo R Temerozo, Andrés Mojoli, Natalia C Rochael, Suwellen S D de Azevedo, Marcos Antonio Formiga-Jr, Gonzalo Bello, Marcelo Ribeiro-Alves, Elvira M Saraiva, Dumith Chequer Bou-Habib.

BACKGROUND: Neutrophils play key roles in innate immune responses and can release extracellular traps (NETs), characterized by chromatin exteriorization associated with cytoplasmic and granule proteins, such as neutrophil elastase, myeloperoxidase, HMGB1, and S100 family. These traps are released upon neutrophil activation by several factors, including inflammatory mediators and infectious agents. Since NETs interact with macrophages in various tissues in physiological contexts or pathological conditions, we aimed to elucidate the molecular mechanisms underlying cellular activation upon this interaction.
METHODS: Human monocyte-derived macrophages from healthy donors were in vitro exposed to NETs induced by the inactivated viruses HIV-1 (inHIV) or SARS-CoV-2 (inSARS), and ELISA was used to analyze the production of inflammatory mediators. The involvement of Toll-like receptors (TLRs) and the engaged signaling pathway was elucidated using pharmacological inhibitors. RNA sequencing was applied to analyze the transcriptional profile of macrophages exposed to IL-8-induced NETs.
RESULTS: NETs increased macrophage production of reactive oxygen species and promoted NF-κB activation. Furthermore, NETs induced the release of the β-chemokines MIP-1α, MIP-1β, and RANTES, as well as the cytokines IL-6, IL-8, IL-10, and TNF-α. The inhibition of TLR2, TLR4, and NF-κB signaling abrogated macrophage production of inflammatory mediators induced by NETs. NET-mediated macrophage activation was also reduced upon inhibition of protein kinase A and blockade of actin polymerization, suggesting that both pathways are required for NET effects. RNA-seq revealed that 406 genes were differentially expressed, such as chemokines, transcription factors and metabolism-related genes. Gene Ontology analysis showed ten biological processes, six cellular components and seven molecular functions enriched in NET-treated macrophages, including chemoattractant activity, regulation of protein kinase activity, protein phosphorylation, and response to oxygen levels.
CONCLUSIONS: Our findings show that NETs modulate the macrophage transcriptional profile and function through TLR2 and TLR4 engagement, and PKA and NF-kB recruitment.

DOI: https://doi.org/10.1186/s12964-026-02951-8