bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–01–25
nine papers selected by
Kateryna Shkarina, Universität Bonn
  1. Poxvirus dsDNA genomes differentially activate AIM2 or NLRP3 inflammasomes in human primary cells.
  2. Differential targeting of human pyroptotic Caspase-5 and Caspase-4 by Shigella OspC2 and OspC3.
  3. Molecular mechanism of MDA5 nucleation and filament formation by LGP2.
  4. Calcium signaling regulates apoptosis-induced proliferation in Drosophila.
  5. Dead but not gone: the interplay between the programmed cell death process and surrounding bacteria.
  6. Cell viscosity influences haematogenous dissemination and metastatic extravasation of tumour cells.
  7. Rift Valley fever virus activates multiple cell death pathways in neurons.
  8. NETosis mediates tick blood pool formation.
  9. The transition from monocyte to tissue-resident macrophage requires DHPS.
  1. EMBO J. 2026 Jan 20.
    Poxvirus dsDNA genomes differentially activate AIM2 or NLRP3 inflammasomes in human primary cells.
    Yonas M Tesfamariam, Maria H Christensen, Stefan Diehl, Tabea Klein, Julius M Lingnau, Sabine Normann, Elena Hagelauer, Miriam Herbert, Sophie Reimer, Richa P Joshi, Pujan Engels, Steffen Pritzl, Pietro Fontana, Thomas Zillinger, Gunther Hartmann, Anna Eis-Hübinger, Martin C Lam, Klaus J Walgenbach, Felix Meissner, Hao Wu, Florian I Schmidt.
      The innate immune system is known for its ability to recognize cytosolic DNA as evidence of infection, but detailed studies of this process have been mostly limited to mice and cell lines. To investigate inflammasome responses in human primary cells, we used engineered viruses encoding the inflammasome reporter caspase-1CARD-EGFP. We show that released genomes of vaccinia virus and monkeypox virus trigger robust inflammasome assembly in human primary cells. To determine the involved inflammasome sensors, we generated nanobodies against AIM2. Three of them inhibit AIM2 inflammasome assembly by blocking the polymerization of the AIM2 Pyrin domain, most potently as bivalent nanobodies. Utilizing an engineered vaccinia virus expressing bivalent AIM2 nanobodies, we demonstrate that inflammasomes in primary human macrophages and keratinocytes are nucleated by AIM2, while CD14+ monocytes assemble NLRP3 inflammasomes. This finding resolves the discrepancy between the previously reported activation of AIM2 inflammasomes in mice and NLRP3 inflammasomes in humans, and provides the first evidence for cell-type-specific regulation of DNA-triggered inflammasome activation. The newly developed AIM2-specific nanobodies offer a precise tool to dissect and potentially target AIM2 inflammasome assembly in other disease contexts.
    Keywords:  AIM2; Inflammasome; NLRP3; Nanobody; Poxvirus
    DOI:  https://doi.org/10.1038/s44318-025-00690-z
  2. bioRxiv. 2025 Dec 04. pii: 2025.12.04.692159. [Epub ahead of print]
    Differential targeting of human pyroptotic Caspase-5 and Caspase-4 by Shigella OspC2 and OspC3.
    Kyungsub Kim, Marcos Antonio Valdespino Diaz, Rowan Karr, Michele E Muscolo, Lisa Goers, Truelian Yu, Tera C Levin, Jonathan N Pruneda, Cammie F Lesser.
      Pyroptosis is an inflammatory cell death pathway that is a key defense mechanism of intestinal epithelial cells. To successfully establish an infection, intracytosolic Gram-negative pathogens must block this host response. Indeed, Shigella OspC3 suppresses epithelial pyroptosis by targeting and inactivating Caspase-4 (CASP4). Here, we demonstrate that OspC2, which shares 96% identity with OspC3, targets Caspase-5 (CASP5), a close paralog of CASP4. Through a combination of yeast two-hybrid, transfection, and bacterial infection assays, we show that the distinct pyroptotic caspase specificities of OspC2 and OspC3 are determined by a short α-helical region, designated the P yroptotic C aspase S pecificity (PCS) domain. This domain is located upstream from the A nkyrin R ich R epeat (ARR) region previously established to promote OspC3 binding to CASP4. Swapping PCS domains between OspC2 and OspC3 is sufficient to redirect their caspase targeting. Evidence for CASP5-driven pyroptosis in response to infection has not yet been established. However, CASP5 displays signatures of positive selection at residues predicted to interact with the PCS domain of OspC2. Notably, the introduction of orangutan-specific residues into human CASP5 disrupt its interaction with and modification by OspC2, demonstrating that CASP5 natural variation can cause key functional differences in this host-microbe molecular interaction. These findings highlight the evolutionary interplay between bacterial effectors and host proteins, support a likely role for CASP5 in responding to Gram-negative bacteria, and identify promising therapeutic targets for enhancing epithelial defense against bacterial pathogens.
    Importance: Shigella species are human-specific Gram-negative pathogens that establish a replicative niche in intestinal epithelial cells by blocking pyroptosis, a key inflammatory cell death pathway. We reveal that two closely related Shigella type III secreted effectors, OspC2 and OspC3, specifically inactivate the human caspase paralogs CASP5 and CASP4, respectively. This specificity is determined by their newly identified Pyroptotic Caspase Specificity (PCS) domains. In addition, we find that positively selected residues in CASP5 alter the OspC2/CASP5 interaction, underscoring the impacts of ongoing evolutionary arms races between bacterial effectors and host immune proteins. By elucidating the molecular basis of caspase targeting and adaptation, this work provides new insight into the diversification of host defense mechanisms and identifies potential therapeutic targets for enhancing epithelial resistance to bacterial infection.
    DOI:  https://doi.org/10.64898/2025.12.04.692159
  3. Mol Cell. 2026 Jan 19. pii: S1097-2765(25)01017-2. [Epub ahead of print]
    Molecular mechanism of MDA5 nucleation and filament formation by LGP2.
    Nina Kurihara, Yukari Isayama, Jiayan Zhang, Takashi Yamashita, Kentaro Awaji, Yukiko Ito, Ayumi Yoshizaki, Takahisa Kouwaki, Hiroyuki Oshiumi, Hiroshi Nishimasu, Mikihiro Shibata, Osamu Nureki, Kazuki Kato.
      LGP2, a RIG-I-like receptor, plays a crucial role in antiviral immunity by enhancing MDA5 activity against specific viral infections. Here, using biochemical assays, cryo-electron microscopy (cryo-EM), and high-speed atomic force microscopy, we reveal that LGP2 initially binds to the ends of double-stranded RNA (dsRNA) and subsequently translocates along the RNA via ATP hydrolysis. Our cryo-EM structure demonstrates that LGP2 forms filament-like assemblies with MDA5 along the internal region of dsRNA, promoting MDA5 filament nucleation. Additionally, LGP2 and MDA5 form short RNA filaments, which are further cross-bridged via caspase activation and recruitment domain (CARD)-CARD interactions, leading to the formation of filament microclusters. These microclusters, in turn, stimulate mitochondrial antiviral signaling (MAVS) filament formation. Our findings uncover a dynamic interplay between LGP2 and MDA5, revealing a previously unrecognized mechanism that enhances antiviral immune responses.
    Keywords:  LGP2; MAVS; MDA5; RIG-I; innate immunity; viral infection
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.019
  4. PLoS Biol. 2026 Jan 20. 24(1): e3003607
    Calcium signaling regulates apoptosis-induced proliferation in Drosophila.
    Komal Panchal Suthar, Caitlin Hounsell, Yun Fan, Andreas Bergmann.
      Caspases, traditionally viewed as mediators of apoptosis and tumor suppressors, have also been shown to promote cell proliferation and to contribute to tumor growth. For example, the initiator caspase Dronc (the Drosophila orthologue of Caspase-9) can trigger apoptosis-induced proliferation (AiP), a process where apoptotic cells generate mitogenic signals for compensatory proliferation independently of their apoptotic function. AiP is crucial for homeostatic cell turnover, wound healing, and tissue regeneration. Previously, we established that Dronc activates the NADPH oxidase DUOX at the plasma membrane, resulting in the production of extracellular reactive oxygen species (ROS) which are required for AiP. However, the mechanism by which Dronc activates DUOX has remained elusive. Here, we identified Dronc-dependent Ca2+ entry into the cytosol as a significant factor for DUOX activation and AiP. Three cell surface Ca2+ channels of the TRP family mediate Ca2+ influx in a non-redundant fashion. Additionally, calcium-induced calcium release (CICR) from the ER was identified as another source of cytosolic Ca2+ during AiP. Notably, DUOX itself acts as a Ca2+ effector in AiP, requiring Ca2+ binding for its activation. These findings highlight the importance of Ca2+ signaling in AiP and provide insights into how similar signaling mechanisms might operate in vertebrates.
    DOI:  https://doi.org/10.1371/journal.pbio.3003607
  5. Infect Immun. 2026 Jan 21. e0050924
    Dead but not gone: the interplay between the programmed cell death process and surrounding bacteria.
    Sam Benson, Christopher J Anderson.
      Cell death is an integral part of homeostasis, removing damaged and infected cells and replenishing healthy cells. It is a process well understood from a host perspective, with clearly delineated pathways and an expansive literature as to how it interacts with other immune and tissue mechanisms. However, the interaction between cell death and the microbial community is less well explored. There is an understanding of how bacterial pathogens are able to induce death and can have a detrimental impact on tissue resolution and repair but little on how bacteria respond to homeostatic cell death or death caused by non-bacterial stimuli. This review will cover recent advances in the understanding of host-microbe communication during cell death and will discuss how bacteria modulate/are modulated by cell death-related phenomena. The interplay between the microbiota and the fundamental processes involved in host cell death presents an exciting opportunity to discover how modulation of host mechanisms can beneficially modulate the microbiota, and therefore concurrently offer potential routes to control a number of conditions that have been linked to aberrant microbiota composition, including inflammatory bowel disease and cancer.
    Keywords:  NETosis; apoptosis; cell death; efferocytosis; ferroptosis; gut microbiota; necroptosis; oral microbiota; pyroptosis
    DOI:  https://doi.org/10.1128/iai.00509-24
  6. Nat Mater. 2026 Jan 19.
    Cell viscosity influences haematogenous dissemination and metastatic extravasation of tumour cells.
    Valentin Gensbittel, Zeynep Yesilata, Louis Bochler, Gautier Follain, Laurie Nemoz-Billet, Olivier Lefebvre, Klemens Uhlmann, Annabel Larnicol, Giulia E M Ammirati, Sébastien Harlepp, Ruchi Goswami, Salvatore Girardo, Laetitia Paulen, Vincent Hyenne, Vincent Mittelheisser, Tristan Stemmelen, Anne Molitor, Raphael Carapito, Guillaume Belthier, Julie Pannequin, Martin Kräter, Daniel J Müller, Daniel Balzani, Jochen Guck, Naël Osmani, Jacky G Goetz.
      Metastases arise from a multistep process during which tumour cells face several microenvironmental mechanical challenges, which influence metastatic success. However, how circulating tumour cells (CTCs) adapt their mechanics to such microenvironments is not fully understood. Here we report that the deformability of CTCs affects their haematogenous dissemination and identify mechanical phenotypes that favour metastatic extravasation. Combining intravital microscopy with CTC-mimicking elastic beads, mechanical tuning in tumour lines and profiling of tumour-patient-derived cells, we demonstrate that the inherent mechanical properties of circulating objects dictate their ability to enter constraining vessels. We identify cellular viscosity as a rheostat of CTC circulation and arrest, and show that cellular viscosity is crucial for efficient extravasation. Moreover, we find that mechanical properties that favour extravasation and subsequent metastatic outgrowth can be opposite. Altogether, our results establish CTC viscosity as a key biomechanical parameter that shapes several steps of metastasis.
    DOI:  https://doi.org/10.1038/s41563-025-02462-w
  7. J Virol. 2026 Jan 22. e0174225
    Rift Valley fever virus activates multiple cell death pathways in neurons.
    Kaleigh A Connors, Zachary D Frey, Matthew J Demers, Morgan Midgett, Connor Williams, Douglas S Reed, Zachary P Wills, Amy L Hartman.
      Neuronal injury and death contribute to long-term impairments and lethality during viral encephalitis. Rift Valley fever virus (RVFV), an arbovirus with epidemic potential, can manifest as late-onset encephalitis in humans, yet this disease outcome remains understudied. A lethal rodent model of RVF encephalitis is characterized by a dysregulated immune response, neuronal necrosis, and blood-brain barrier breakdown that precedes lethality. In this study, we built upon this prior work using both in vivo and in vitro models to interrogate the mechanism of cell death in neurons during RVFV infection. We found an increase in proteins associated with apoptosis, pyroptosis, and necroptosis in the brains of animals that succumb to lethal RVFV encephalitis. We then focused on identifying the primary cell death pathways in primary cortical neurons, which were highly susceptible to infection by pathogenic and attenuated viral strains. Using immunoblotting, immunocytochemistry, and in-cell western assays, we found that neurons infected with RVFV resulted in the activation of multiple cell death pathways, leading to neuron cell death. These findings further our understanding of the impact of RVFV infection, which is critical to identifying therapeutics that support neuron integrity and minimize injury during viral encephalitis.IMPORTANCERift Valley fever may be accompanied by late-onset encephalitis in humans. Our lab has studied the in vivo mechanisms of neurological disease, yet the precise mechanisms of cell death in the central nervous system have been elusive. An understanding of the how and why of cell death from Rift Valley fever virus (RVFV) infection may guide the design of therapeutic interventions. Here, we use primary neurons to probe the mechanism of cell death following RVFV infection. We found that RVFV triggers multiple cell death pathways both in the brains of animals that succumb to lethal RVFV encephalitis as well as in ex vivo neuronal cultures. Induction of cell death occurs even with infection by an attenuated vaccine strain. These findings provide a platform for understanding cell death mechanisms caused by RVFV infection and identifying therapeutics that support neuron integrity during viral encephalitis.
    Keywords:  PANoptosis; Phenuiviridae; Rift Valley fever; bunyavirus; cell death; neuron; viral encephalitis
    DOI:  https://doi.org/10.1128/jvi.01742-25
  8. J Vet Med Sci. 2026 Jan 20.
    NETosis mediates tick blood pool formation.
    Yuki Koike, Hayato Kawada, Sana Sasaki, Kei Jimbo, Keiko Mizutani, Kofi Dadzie Kwofie, Fusako Mikami, Hirotomo Kato, Makoto Matsubayashi, Naotoshi Tsuji, Takeshi Hatta.
      Ticks are major public health vectors that rely on long-term extravascular feeding, a process critically dependent on establishing a subcutaneous blood pool. While tick salivary molecules suppress host hemostasis and immunity, the precise mechanism by which vascular integrity is compromised to sustain massive hemorrhage in the deep dermis, outside the tick hypostome's reach, remains a longstanding enigma. Using time-series pathological and multiplex immunohistochemical analyses in a mouse model infected with Haemaphysalis longicornis tick, we redefined the blood pool not as a cystic reservoir, but as a severe inflammatory lesion characterized by massive, diffuse extravasation of red blood cells. We observed that ticks induce pathological angiogenesis, forming fragile microvessels. Crucially, the formation of neutrophil extracellular traps (NETs), known as NETosis surged in clustering neutrophils on Day 3 of feeding, coinciding with the transition to massive hemorrhage. Furthermore, extravasated platelets co-localized with NETs in the hemorrhagic tissue. We propose a sophisticated parasitic strategy, whereby the tick hijacks host immunothrombosis to mediate massive hemorrhage. The dysregulated interaction between NETs and platelets drives a vicious inflammatory cycle, which destroys the fragile, newly formed vasculature and extracellular matrix. This process establishes a blood-soaked, sponge-like stroma, which the tick exploits for efficient blood intake. Our findings redefine the fundamental mechanism of tick feeding success.
    Keywords:  blood pool; netosis; neutrophil extracellular trap-platelet interaction; platelet; tick
    DOI:  https://doi.org/10.1292/jvms.25-0591
  9. Nature. 2026 Jan 21.
    The transition from monocyte to tissue-resident macrophage requires DHPS.
    Gustavo E Carrizo, Pianpian Lin, Seung Hyun Lee, Kevin Shenderov, Camille Blériot, Minsun Cha, Lena Schimmelpfennig, Zhen Shen, Nikki van Teijlingen Bakker, Katarzyna M Grzes, Beth Kelly, Niloufar Safinia, Kate L Schole, Yaarub Musa, Gerhard Mittler, Yoh Zen, Edward J Pearce, Florent Ginhoux, David E Sanin, Daniel J Puleston, Erika L Pearce.
      Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris1-6. During tissue damage, however, bone-marrow-derived monocytes enter tissues and differentiate into RTMs, repairing the tissue and replenishing macrophages in the niche1. The universal cell-intrinsic mechanisms that control the monocyte-to-RTM transition and the maintenance of mature RTMs across tissues remain elusive3. Here we show that deoxyhypusine synthase (DHPS), an enzyme that mediates spermidine-dependent hypusine modification of translation factor eIF5A5,7, is required for RTM differentiation and maintenance. Mice with myeloid cell lack of DHPS (Dhps-ΔM mice) had a global defect in RTMs across tissues, resulting in persistent but ultimately futile monocyte influx. Transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature RTMs, whereas proteomics revealed defects in cell adhesion and signalling pathways. Sequencing of ribosome-engaged transcripts identified a subset of mRNAs involved in cell adhesion and signalling that rely on DHPS for efficient translation. Imaging of DHPS-deficient macrophages in tissues showed differences in morphology and tissue interactions, which were correlated with their failed RTM differentiation. DHPS-deficient macrophages were also defective in critical homeostatic RTM functions including efferocytosis and tissue maintenance. Together, our results demonstrate a cell-intrinsic, tissue-agnostic pathway that drives differentiation of monocyte-derived macrophages into RTMs.
    DOI:  https://doi.org/10.1038/s41586-025-09972-2
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