bims-cediti 2026-05-10 papers

bims-cediti

Biomed News

on Cell death in innate immunity, inflammation, and tissue repair

Issue of 2026–05–10
ten papers selected by
Kateryna Shkarina, Universität Bonn

Inflammasome adaptor protein ASC is a mechanistic checkpoint in IL-1β maturation.
An overview of human inflammasomes: Activation and regulation.
Streptococcus anginosus Activates the NLRP3 Inflammasome to Promote Inflammatory Responses from Macrophages.
Unbiased proteomics following inflammasome activation identifies caspase targets in primary intestinal epithelial cells.
Cell death modalities modulate inflammatory and regenerative programs in zebrafish sensory organs.
Comparative insights into the apoptosome, inflammasomes and PIDDosome.
A century of cell death research.
Current understanding of the NLRC4 Inflammasome in autoinflammation and enterocolitis.
Disruption of macrophage cell volume drives inflammatory responses and type I interferon signaling.
Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution.

Proc Natl Acad Sci U S A. 2026 May 12. 123(19): e2537563123

Inflammasome adaptor protein ASC is a mechanistic checkpoint in IL-1β maturation.

Giti Saha, Pratibha Anchi, Richard Wang, Alyssa Biondo, Sadie Meyer, Vinata Kondragunta, Larry L Luchsinger, Ismail Syed, Humayun Sharif, Hao Wu, Venkat Giri Magupalli.

  Inflammasome activation triggers caspase-1-dependent maturation of pro-interleukin-1β (pro-IL-1β) in an apoptosis-associated speck-like protein containing a CARD (ASC)-dependent manner, yet the mechanism by which pro-IL-1β is physically recruited to the ASC signaling platform has remained undefined. Here, we identify the ASC linker domain (ASCLD) as a noncanonical protein-interaction interface, that can directly recruits pro-IL-1β onto the ASC speck. Using a live-cell NanoBRET assay, confocal imaging, and pulldown analysis, we show that ASC directly engages pro-IL-1β and that this interaction requires a discrete set of charged residues in the IL-1β mature domain region, forming an ASC-docking surface. Mutagenesis guided by the IL-1β structure confirmed that this interaction is essential for caspase-1-dependent IL-1β maturation but dispensable for pyroptosis. Domain mapping revealed that ASCLD, rather than its N-terminal Pyrin domain (PYD) or C-terminal caspase recruitment domain (CARD), mediates pro-IL-1β recruitment. Using an in-house custom antibody against ASCLD, we show that this region remains exposed within endogenous ASC specks in macrophages. Mutational disruption of ASCLD selectively impaired IL-1β processing in THP-1 cells Mutations disruption data was obtained from THP-1 cells without affecting ASC speck formation or pyroptosis. A cell-penetrating peptide derived from ASCLD selectively blocked pro-IL-1β docking while preserving speck assembly. In 2 mouse models of peritonitis, the blocking peptide uncoupled cytokine maturation from pyroptosis and significantly reduced IL-1β-driven inflammation. Thus, our findings uncover ASCLD as a critical docking interface that positions pro-IL-1β for efficient caspase-1 processing, which adds a mechanistic checkpoint within inflammasomes to license cytokine maturation independently of pyroptotic death. We propose that ASCLD may be a therapeutically tractable node for selective modulation of IL-1β-driven inflammasomopathies.

Keywords:  IL-1β; inflammasomes; pyroptosis

DOI:  https://doi.org/10.1073/pnas.2537563123
J Immunol. 2026 Apr 15. pii: vkag081. [Epub ahead of print]215(4):

An overview of human inflammasomes: Activation and regulation.

Elisabeth Jäger, Sana Ismaeel, Christian Stehlik, Andrea Dorfleutner.

  The innate immune system has evolved as the primary response mechanism against microbial infections, tissue damage, and cellular stress. Signals that disrupt homeostasis are sensed by pattern recognition receptors and initiate innate immune responses to restore homeostasis. Some intracellular pattern recognition receptors belonging to the Nod-like receptor, AIM2-like receptor, and pyrin family initiate the assembly of a multiprotein signaling platform called inflammasome. Subsequent protease activation enables maturation and secretion of the proinflammatory cytokines interleukin-1β and interleukin-18 and initiation of a proinflammatory cell death, called pyroptosis. Importantly, inflammasome dysregulation is involved in numerous diseases. While many inflammasomes are evolutionary highly conserved, some species have unique sensor proteins and unique regulatory mechanisms. Recently, significant characteristics of human inflammasomes and their regulation have been identified. These exciting insights into human inflammasome biology will be crucial for our efforts to understand human physiology and to develop inflammasome-based treatment strategies. Here, we highlight distinct features of human inflammasomes.

Keywords:  cytokine; human; inflammasome; innate immunology; pyroptosis

DOI:  https://doi.org/10.1093/jimmun/vkag081
J Leukoc Biol. 2026 May 08. pii: qiag061. [Epub ahead of print]

Streptococcus anginosus Activates the NLRP3 Inflammasome to Promote Inflammatory Responses from Macrophages.

Anika M Arias, Dakota M Reinartz, Chloe Sairs, Sangeetha Senthil Kumar, Harrison C Byrnes, Justin E Wilson.

  Chronic inflammation and oral dysbiosis are common features of oral squamous cell carcinoma (OSCC). The commensal streptococci, S. anginosus, is increased in oral diseases including OSCC. Our previous work revealed that S. anginosus promotes inflammatory responses from macrophage cell lines, however the molecular mechanism by which S. anginosus interacts with macrophages to instigate this response remains to be investigated. Here, we found S. anginosus activated primary bone marrow derived macrophages (BMMs), which presented increased NF-κB activation and downstream inflammatory cytokines TNF⍺, IL-6 and IL-1β at 24 hours post-infection. S. anginosus viability, TLR2, TLR4 and MyD88 were dispensable for NF-κB activation, but each promoted the induction of distinct downstream inflammatory mediators, with only MyD88 being necessary for NF-κB activation in response to heat-killed S. anginosus. S. anginosus replicated intracellularly within BMMs without causing cell death and induced expression of inflammasome sensors AIM2, NLRC4 and NLRP3. S. anginosus-infected BMMs lacking the inflammasome adapter protein ASC (Asc-/-) or Caspase-1 (Caspase1-/-) had significantly diminished IL-1β production compared to wild type BMMs, indicating that S. anginosus activated the inflammasome. S. anginosus primarily triggered the inflammasome through NLRP3 as S. anginosus-infected Nlrp3-/- BMMs and NLRP3 inhibitor (MCC950)-treated wild type BMMs displayed diminished IL-1β production compared to wild type controls. Lastly, S. anginosus-infected Asc-/- and to a lesser extent Nlrp3-/- mice displayed reduced weight loss, reduced inflammatory cytokines, and increased bacterial burden compared to C57BL/6 mice. These findings indicate that S. anginosus replicates within macrophages and promotes a proinflammatory response in part through activating the NLRP3 inflammasome.

Keywords:   Streptococcus anginosus ; NLRP3 Inflammasome; macrophages

DOI:  https://doi.org/10.1093/jleuko/qiag061
bioRxiv. 2026 Apr 22. pii: 2026.04.20.719683. [Epub ahead of print]

Unbiased proteomics following inflammasome activation identifies caspase targets in primary intestinal epithelial cells.

Alexis R Gibson, Ivo Diaz Ludovico, Geremy C Clair, Chelsea M Hutchinson-Bunch, Joshua Adkins, Isabella Rauch.

Inflammasomes are cytosolic innate immune sensors that, once activated by a pathogenic threat, lead to activation of the inflammatory Caspase-1. Inflammasome activation and its consequences have been studied extensively in myeloid cells and in overexpression systems. Recent studies have identified cell type specific effects that are not fully explained by the known cleavage targets of Caspase-1. Here, we identified targets of caspase cleavage using mass spectrometry in primary intestinal epithelial cells by specifically activating the NAIP-NLRC4 inflammasome. We have taken an unbiased approach and developed a novel method for analyzing mass spectrometry data for evidence of caspase activity. Our approach can also be applied to existing proteomic datasets to establish the presence of caspase activity under various biological conditions. These results lay the groundwork for future studies on mechanisms of caspase-induced processes such as intestinal epithelial cell extrusion.

DOI: https://doi.org/10.64898/2026.04.20.719683
Nat Commun. 2026 May 07.

Cell death modalities modulate inflammatory and regenerative programs in zebrafish sensory organs.

Daniela Münch, Shiyuan Chen, Elizabeth Ellis, Nicolas Denans, Mark E Lush, Kaitlyn Petentler, Jose E Javier, KyeongMin Bae, Tatjana Piotrowski.

Regeneration is triggered by cells dying due to various types of injuries. However, it remains unclear whether different types of cell death elicit distinct regeneration responses. Here, we systematically profile dynamic transcriptional responses of macrophages and lateral line cells to different cell death modalities during zebrafish sensory hair cell regeneration. We show that chemogenetically induced programmed hair cell death triggers a diminished inflammatory response compared to pharmacologically induced cell lysis, characterized by minimal neutrophil recruitment, distinct transcriptional profiles in phagocytosing macrophages and reduced expression of injury-responsive genes in lateral line cells. Nevertheless, regeneration ultimately converges on a shared set of regeneration-specific genes. Importantly, preventing immune cell recruitment enhances injury-induced support cell proliferation in response to programmed, but not unprogrammed cell death, highlighting cell death-dependent regenerative outcomes following immune cell inhibition. Our findings demonstrate that different forms of cell death trigger distinct molecular events, with implications for tailoring regenerative therapies to specific injury contexts.

DOI: https://doi.org/10.1038/s41467-026-72517-2
Nat Rev Immunol. 2026 May 06.

Comparative insights into the apoptosome, inflammasomes and PIDDosome.

Mohamed Lamkanfi, Lieselotte Vande Walle, Felix Eichin, Andreas Villunger.

Caspase activation platforms such as the apoptosome, inflammasome and PIDDosome are central to cellular responses to stress, coordinating inflammation, cell death and cell differentiation. Although each of these complexes has been extensively studied in isolation, a comparative understanding of their structural and functional principles is lacking. Here we provide an integrated review of the architecture, activation mechanisms and signalling outputs of these supramolecular signalling platforms. All three of these platforms share a broadly conserved domain architecture and promote proximity-induced caspase activation, but they differ in their subcellular localization and upstream triggers. Furthermore, we explore differences in their downstream effectors and roles in immune signalling, cell cycle regulation and tissue homeostasis. Germline mutations in humans affecting these complexes are linked to cancer predisposition, immune dysregulation and neurodevelopmental disorders, respectively. Finally, we discuss therapeutic opportunities and unresolved questions, aiming to stimulate cross-disciplinary research and translational applications.

DOI: https://doi.org/10.1038/s41577-026-01304-3
J Cell Sci. 2026 May 01. pii: jcs264578. [Epub ahead of print]139(9):

A century of cell death research.

Douglas R Green.

  The fact that cells die during development, metamorphosis and tissue homeostasis was recognized well over a century ago. However, aside from noting and classifying such cell death events, research into the mechanisms of regulated cell death did not 'take off' until about 35 years ago. Since then, our understanding of the different ways that cells die and how this comes about has blossomed. In celebration of the 100-year anniversary of the Journal of Cell Science's publisher The Company of Biologists, this Perspective article presents an overview of the past 100-plus years of cell death research, touching on the history of apoptosis, necroptosis and other forms of cell death.

Keywords:  Apoptosis; Ferroptosis; Necroptosis; Pyroptosis

DOI:  https://doi.org/10.1242/jcs.264578
Commun Biol. 2026 May 05. pii: 611. [Epub ahead of print]9(1):

Current understanding of the NLRC4 Inflammasome in autoinflammation and enterocolitis.

Yuhang Wang, Sivakumar Lingappa, Zizhen Kang.

The NLRC4 inflammasome is a cytosolic immune sensor that detects bacterial virulence structures and rapidly initiates inflammatory responses. While tightly regulated NLRC4 activation is essential for host defense, genetic mutations that enhance NLRC4 signaling can drive severe autoinflammatory disease. Studies in patients and genetically engineered mouse models have begun to reveal how dysregulated NLRC4 activation disrupts intestinal and systemic immune homeostasis. This review summarizes current insights into NLRC4-associated autoinflammatory diseases, with particular emphasis on the mechanisms underlying autoinflammation with infantile enterocolitis, and highlights emerging concepts related to disease heterogeneity and therapeutic targeting.

DOI: https://doi.org/10.1038/s42003-026-10174-3
J Cell Biol. 2026 Jun 01. pii: e202411133. [Epub ahead of print]225(6):

Disruption of macrophage cell volume drives inflammatory responses and type I interferon signaling.

James R Cook, Tara A Gleeson, Sara Gago, Stuart M Allan, Kevin N Couper, Catherine B Lawrence, David Brough, Jack P Green.

Macrophages coordinate inflammatory and immune responses to threats, yet how they interpret diverse danger signals to tailor inflammation remains unclear. Disturbances in extracellular and intracellular homeostasis alter cell volume, but the consequences for macrophage inflammatory responses are poorly understood. We demonstrate that macrophages use cell volume control as a danger-sensing mechanism to promote and augment inflammation. Using volume-regulated anion channel (VRAC)-deficient macrophages, which lack cell volume control under hypo-osmotic conditions, we show that cell volume disruptions drive transcriptomic reprogramming and induction of inflammation. Cell volume disruption induced type I interferon signaling through a DNA- and TBK1-dependent mechanism, but independent of cGAS and 2'3'-cGAMP transport. VRAC deficiency enhanced macrophage antiviral responses to influenza infection. Cell volume changes synergized with diverse pathogen-associated molecular pattern-mediated signaling to augment type I interferon responses and exacerbate the cytokine storm in mouse models of hyperinflammation. Our findings highlight cell volume as an important regulator in shaping inflammatory responses, expanding our understanding of how macrophages sense complex danger signals.

DOI: https://doi.org/10.1083/jcb.202411133
bioRxiv. 2026 Apr 30. pii: 2026.04.27.720940. [Epub ahead of print]

Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution.

David Ngai, Saheli Chowdhury, George Kuriakose, Brian Havens, Santosh R Sukka, Mustafa Yalcinkaya, Jeremy M Frey, Heather Doviak, Jennifer W Bradford, Bernhard Dorweiler, Hanna Winter, Lars Maegdefessel, Kenneth Walsh, Joshua P Thaler, Alan R Tall, Ira Tabas.

The clearance of apoptotic cells by macrophages, termed efferocytosis, reprograms macrophages to a resolution/repair phenotype, and pathologic defects in efferocytosis drive many chronic inflammatory diseases. Previous studies have elucidated numerous downstream pro-resolving pathways activated by efferocytosis, but whether there exists a common upstream trigger of these pathways remains unknown. Here, we report that efferocytosing macrophages surprisingly use a signaling module typically associated with inflammation to carry out this key initiating role in tissue resolution. The binding of apoptotic cells to the MerTK receptor triggers a rapid and transient activation of inhibitor of nuclear factor (NF) kappa-B kinase subunit beta (IKKβ), leading to NFκB and p38-signal transducer and activator of transcription 3 (STAT3) signaling and then activation of several key downstream pro-resolving pathways, including interleukin-10 (IL-10) production, continuing efferocytosis, and regulatory T (T reg ) cell expansion. The upstream IKKβ pathway and the downstream resolution pathways are linked through several intermediary molecules, including the transcription factor Myc, the epigenetic modifier ten-eleven translocation-2 (TET2), and the immune checkpoint protein programmed cell death ligand 1 (PD-L1). Deletion of macrophage IKKβ in vivo blocks the above resolution pathways and compromises tissue repair in two efferocytosis-mediated repair settings: resolution of thymic injury after dexamethasone-induced thymocyte apoptosis; and, most importantly, atherosclerosis regression induced by low-density lipoprotein (LDL)-lowering, which is highly relevant to the prevention of cardiovascular disease in humans. These findings illustrate the existence of a unifying upstream signal for efferocytosis-induced resolution, which could suggest new therapeutic strategies to enhance multiple tissue resolution pathways and to optimize anti-inflammatory therapies by avoiding blocking IKKβ-NFκB/p38-mediated resolution.

DOI: https://doi.org/10.64898/2026.04.27.720940