bims-cediti 2026-04-26 papers

bims-cediti

Biomed News

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

Issue of 2026–04–26
eleven papers selected by
Kateryna Shkarina, Universität Bonn

Caspase-8 mediates E. coli-induced cell death and innate immune responses.
Activation of the NLRP3 inflammasome in osteoclasts is suppressed by a Tmem178-dependent mechanism that restricts Ca2+ influx.
Trifluoperazine causes mast cell apoptosis through a secretory granule-mediated pathway.
ZBP1 mediated restriction of Toxoplasma gondii in both the early acute and chronic brain stages of infection.
Chemotherapy-induced activation of caspase-1 and IL-1α release by cancer cells remotely skews myelopoiesis to drive pro tumorigenic systemic neutrophil-dominant inflammation.
Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
Manipulation of nonclassical ubiquitin signaling by pathogenic bacteria.
PKR condensation at viral replication complexes initiates its activation.
Ligation of TLR2, but not of TLR4 or other Toll-like receptors, induces neutrophil extracellular trap formation in humans.
NEK7 Cys298 is important for NLRP3 inflammasome and targetable by dimethyl fumarate.
Diminished and Altered Cellular Senescence Response in Delayed Wound Healing of Aging.

J Immunol. 2026 Apr 15. pii: vkag037. [Epub ahead of print]215(4):

Caspase-8 mediates E. coli-induced cell death and innate immune responses.

Zhuodong Chai, Yuqi Zhou, Ling Yang, Yan Zhang, Sukria Hossain, Guoying Zhang, Jiaqian Qi, Ziran Zhang, Toshihiko Shiroishi, Yinan Wei, Zhenyu Li.

  Escherichia coli (E. coli) is a leading cause of invasive bacterial infections in humans. Pathogenic E. coli is not only the major etiological agent of enteric/diarrheal disease and urinary tract infections, but also among the most common causes of sepsis and meningitis. Caspase-8 is known to regulate apoptotic and pyroptotic cell death in response to bacterial and viral infections. Here we demonstrate that caspase-8 plays a critical role in E. coli-induced macrophage apoptosis in vitro and in regulating immune response and host death in vivo. Incubation of mouse bone marrow derived macrophages (BMDMs) with an E. coli K1 strain CE10 triggered robust cell death, which is independent of the NAIP/NLRC4/caspase-1/GSDMD pathway. CE10 stimulation induced caspase-8 activation, and macrophages deficient in caspase-8 and RIPK3, but not RIPK3 alone, were protected from CE10-induced cell death. In an intraperitoneal injection sepsis model, E. coli-induced IL-1β, TNF-α, and IL-6 production was markedly reduced in caspase-8-/-/RIPK3-/- mice, compared with RIPK3-/- or wild type mice. Accordingly, the survival rate was significantly improved in caspase-8-/-/RIPK3-/- mice. Moreover, caspase-8 deficiency attenuated CE10-induced NF-κB activation and cytokine production in BMDMs. Together, our findings identify caspase-8 as a central mediator of E. coli-induced cell death, immune response, and establish its critical contribution to host mortality during E. coli infection.

Keywords:   E. coli ; Caspase-8; apoptosis; inflammation; macrophage

DOI:  https://doi.org/10.1093/jimmun/vkag037
Sci Signal. 2026 Apr 21. 19(934): eaea2753

Activation of the NLRP3 inflammasome in osteoclasts is suppressed by a Tmem178-dependent mechanism that restricts Ca2+ influx.

Khushpreet Kaur, Yael Alippe, Chun Wang, Nicholas P Semenkovich, Mohamed G Hassan, Saumya Bhagat, Kunjan Khanna, Yongjia Li, Nitin Pokhrel, Timothy Peterson, Erica L Scheller, Deborah J Veis, Yousef Abu-Amer, Roberta Faccio, Gabriel Mbalaviele.

Activation of the NLRP3 inflammasome can drive bone resorption by osteoclasts in various inflammatory conditions. Here, we identified Tmem178, a protein that restrains Ca2+ fluxes by limiting SOCE activation, as an inhibitor of NLRP3 inflammasome activation and the bone-resorbing activity of osteoclasts. We found that NLRP3 abundance gradually decreased during osteoclastogenesis but was restored by treatment with the bacterial product LPS. LPS and the NLRP3 activator nigericin stimulated this inflammasome in macrophages, as expected, but not in osteoclasts or their lineage-committed precursors. This differential NLRP3 activation was due to Tmem178, a protein abundant in osteoclasts that suppressed NLRP3 inflammasome nucleation. Accordingly, NLRP3 inflammasome activation was robust in osteoclasts lacking Tmem178 or in wild-type osteoclasts exposed to high Ca2+ concentrations. In vivo studies demonstrated that inflammasome formation was enhanced under conditions in which osteoclasts efficiently release Ca2+ from bone and that deletion of Nlrp3 rescued the osteopenic phenotype characteristic of Tmem178-/- mice. Thus, our results indicate that Tmem178 potently restricts Ca2+ influx in osteoclasts, thereby suppressing NLRP3 inflammasome activation.

DOI: https://doi.org/10.1126/scisignal.aea2753
Cell Death Discov. 2026 Apr 22. pii: 185. [Epub ahead of print]12(1):

Trifluoperazine causes mast cell apoptosis through a secretory granule-mediated pathway.

Marianthi Vraila, Jun Mei Hu Frisk, Animamalar Mayavannan, Mirjana Grujic, Erik Stigare, Adnan Lidian, Jenny Hallgren, Gunnar Pejler.

Mast cells contribute to the pathology of various diseases, in particular allergic conditions. Therefore, it is essential to develop strategies that efficiently prevent their harmful effects under such circumstances. Here, we sought to evaluate the possibility of cell death induction as a potential means of selectively depleting mast cells. Previous work has suggested that mast cells are sensitive to regimes that target their acidic secretory granules, and the aim of this study was therefore to identify novel anti-mast cell compounds that act via a granule-mediated pathway. To this end, we evaluated trifluoperazine, an antipsychotic drug known to present lysosomotropic properties. We demonstrate that trifluoperazine is cytotoxic for mast cells, whereas multiple other cell types were resistant. Trifluoperazine induced mainly apoptotic cell death in mast cells. Further, our data indicate that trifluoperazine acts on mast cells by inducing secretory granule permeabilization. In support of this, trifluoperazine caused granule deacidification, accompanied by cytosolic acidification as well as translocation of tryptase from the secretory granules into the cytosol. Trifluoperazine-induced cell death and subsequent DNA degradation were profoundly abrogated when granule acidification was inhibited by the V-ATPase inhibitor bafilomycin A1, suggesting that the granule acidity has a key role in the cell death mechanism. Moreover, mast cell death in response to trifluoperazine was largely caspase-independent, whereas serine protease activity was shown to promote apoptosis-like vs. necrosis-like cell death. Overall, these findings introduce trifluoperazine as a novel anti-mast cell agent that induces cell death through granule permeabilization. Trifluoperazine may thus be evaluated for therapeutic intervention to ameliorate mast cell-mediated detrimental effects.

DOI: https://doi.org/10.1038/s41420-026-03122-x
Immunohorizons. 2026 Apr 11. pii: vlag015. [Epub ahead of print]10(4):

ZBP1 mediated restriction of Toxoplasma gondii in both the early acute and chronic brain stages of infection.

Lydia Anne Sibley, Isaac William Babcock, Naa Dedee Amadi, Anne Elise Marchildon, Abigail Grace Kelly, Sydney Ann Labuzan, John Robert Lukens, Tajie Heartsong Harris.

  ZBP1 is an innate sensor of nucleic acids in the Z-conformation and regulates immune responses via cell death pathways and nuclear factor κB signaling. Previous work has demonstrated an essential role for ZBP1 in viral restriction; however, the role ZBP1 plays in protection against other pathogens is in early stages of exploration. Toxoplasma gondii is an obligate intracellular parasite that can infect all nucleated cells and establishes a chronic infection of the brain requiring a robust innate and adaptive immune response and multiple cell death pathways for host survival. Importantly, innate sensors of T. gondii infection of the central nervous system are still being defined. Prior work has implicated caspase-1 and caspase-8 in the control of T. gondii in the brain. Because ZBP1 can activate both caspase-1 and caspase-8, we sought to explore the role of ZBP1 during T. gondii infection. During early infection, we found an increase in parasite burden; a decrease in NK1.1+ cell, neutrophil, and monocyte recruitment; and impaired NK1.1+ cell cytokine production in the peritoneum of Zbp1-/- mice. Interestingly, during the early adaptive immune response, the immune cell recruitment defects and impaired parasite control were ameliorated. During the brain stage of infection, ZBP1 regulated parasite restriction and numerous inflammatory responses to infection. Our findings establish ZBP1 as a critical regulator of host defense to T. gondii and highlight the importance of ZBP1 in development of inflammation during both the acute and chronic infection.

Keywords:   Toxoplasma gondii ; ZBP1; neuroinflammation

DOI:  https://doi.org/10.1093/immhor/vlag015
Nat Commun. 2026 Apr 20.

Chemotherapy-induced activation of caspase-1 and IL-1α release by cancer cells remotely skews myelopoiesis to drive pro tumorigenic systemic neutrophil-dominant inflammation.

Stephen Qr Wong, Kazukuni Hayashi, Ethan J Subel, Yung Hsing Huang, Hongbo Gao, Haley E Garcia, Sophie J Porter, Mustafa Karabicici, Xen Ping Hoi, Mark D Alonzo, Armine Kasabyan, Efrosini Tsouko, Crystal S Shin, Lisa Bouchier-Hayes, Dimitrios Korentzelos, Chen Chen, Michael Brooks, Zheng Yin, Renil S Titus, Lan Zhou, Yinan Gong, Yulin Li, Stephen Tc Wong, Ziad El-Zaatari, Dharam Kaushik, Raj Satkunasivam, Fotis Nikolos, Keith S Chan.

While chemotherapy-induced tumor cell death is known to modulate the local immune landscape, its systemic impact on distant bone marrow-a site essential for immune cell maturation-remains underexplored. Here, we show that gemcitabine chemotherapy induces inflammatory caspase-1-dependent pyroptosis in epithelial cancer cells (epiCaspase-1). Despite its inflammatory nature, epiCaspase-1-mediated cell death is non-immunogenic. Clinically, elevated expression of an epiCaspase-1 gene signature correlates with worse patient outcomes. Mechanistically, epiCaspase-1 triggers the noncanonical release of IL-1α through NINJ1 lytic pores, remotely skewing bone marrow hematopoiesis towards granulocyte-monocyte progenitors and mature neutrophil output. This systemic reprogramming elevates the neutrophil-to-lymphocyte ratio (NLR) in both peripheral blood and the local tumor microenvironment. Pharmacological inhibition of caspase-1 and IL-1α disrupts this cascade, normalizes hematopoiesis, and recalibrates NLR by promoting intratumoral CD8+ T cell infiltration and activation, ultimately enhancing chemotherapeutic efficacy. These findings challenge the assumption that inflammatory pyroptosis is inherently immunogenic; instead, it can reshape systemic immune landscape towards a neutrophil-dominant inflammation in the chemotherapy context.

DOI: https://doi.org/10.1038/s41467-026-71471-3
Nature. 2026 Apr 22.

Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.

JRI Live Cell Bank

Caspase 5 (CASP5) is a member of the inflammatory caspase family of cysteine proteases that is involved in inflammation and cell death1-3. CASP5 shares the highest homology with inflammatory CASP4, but whereas CASP4 is essential for noncanonical inflammasome activation, CASP5 is dispensable4-6, and its function remains unknown. Here we show that CASP5 is restricted to the human intestinal epithelium and manifests as three isoforms-CASP5A, CASP5B and CASP5C-among which CASP5C uniquely promotes Wnt signalling, which is essential for epithelial development and regeneration7. We identified dishevelled, which bridges Wnt receptors to the β-catenin destruction complex8, as a prominent CASP5 binding partner in colonic epithelial cells. Dishevelled interacts with the CASP5 catalytic domain through its DEP (dishevelled, EGL-10 and pleckstrin) domain. Lacking the inhibitory caspase activation and recruitment domain (CARD) of CASP5A and CASP5B, CASP5C cleaves the central scaffold protein APC at Asp556 in the Armadillo repeat domain, destabilizing the β-catenin destruction complex and thereby enhancing Wnt signalling. CASP5C expression peaks in transit-amplifying cells, the Wnt-reliant progeny of intestinal stem cells7, whereas CASP5A and CASP5B predominate in mature enterocytes. Endogenous and ectopic CASP5C drive growth of colonic and small intestinal organoids, which is known to require proliferation of transit-amplifying cells9. Furthermore, CASP5C is selectively induced upon intestinal epithelial injury, and its expression is increased in inflammatory bowel disease. Thus, CASP5C is an enzymatic amplifier of Wnt signalling that cleaves APC to sustain proliferation of transit-amplifying cells amid a declining Wnt gradient, safeguarding epithelial renewal. These findings broaden the roles of inflammatory caspases beyond innate immunity, uncovering their contribution to tissue homeostasis.

DOI: https://doi.org/10.1038/s41586-026-10343-8
Curr Opin Microbiol. 2026 Apr 20. pii: S1369-5274(26)00050-0. [Epub ahead of print]91 102756

Manipulation of nonclassical ubiquitin signaling by pathogenic bacteria.

Jasleen Kaur Sidhu, Tomoko Kubori, Jonathan N Pruneda.

Manipulation of the host ubiquitin signaling system is emerging as a common and critical mechanism of virulence among pathogenic bacteria. In some cases, such as the intracellular pathogens Legionella pneumophila and Shigella flexneri, ubiquitin regulation is the focus of a significant proportion of the bacterial repertoire of secreted effectors (10% and 30%, respectively). While many of these bacterial effectors hijack classical aspects of the ubiquitin system, such as proteasomal degradation and immune signaling, others target nonclassical ubiquitin signals that are less well understood. These include so-called atypical polyubiquitin chain types, such as Lys6-linked chains, for which specific regulators and functions within human biology have remained elusive. Recent studies have also identified bacterial manipulation of so-called noncanonical ubiquitination, including modification of non-lysine as well as non-proteinaceous targets. Lastly, in select cases such as L. pneumophila, bacteria can impose an entirely orthogonal form of ubiquitin signaling that looks and behaves nothing like the eukaryotic system. Herein, we will review the most recent discoveries in bacterial manipulation of nonclassical ubiquitin signaling.

DOI: https://doi.org/10.1016/j.mib.2026.102756
Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00368-2. [Epub ahead of print]45(5): 117290

PKR condensation at viral replication complexes initiates its activation.

Ebba K Blomqvist, Nicole Bracci, Helena Winstone, J Monty Watkins, Susan R Weiss, James M Burke.

  Protein kinase R (PKR) is a critical component of mammalian intracellular antiviral immunity. Here, we examine the process of PKR activation in response to Middle East respiratory syndrome coronavirus (MERS-CoV) and Zika virus (ZIKV) using super-resolution confocal microscopy, proximity ligation assay, immunogold transmission electron microscopy, and live-cell imaging. Our data support that PKR activates upon condensation on double-stranded RNA (dsRNA) exposed at membrane-associated viral replication complexes. Subsequently, p-PKR condensates disassociate from dsRNA and dissolve, releasing activated PKR molecules into the cytosol, where they phosphorylate eIF2α to initiate the integrated stress response (ISR). Importantly, the disassociation of p-PKR from dsRNA allows for the exchange of inactive PKR monomers, thus promoting robust PKR activation from limited exposed viral dsRNA substrates. MERS-CoV NS4a prevents PKR activation via competitive condensation on viral dsRNA. These findings establish a comprehensive model for PKR activation in response to positive-strand RNA viruses that replicate within membrane-associated complexes.

Keywords:  CP: microbiology; CP: molecular biology; DRIF; MERS-CoV; NS4a; PKR; Zika virus; condensation; dsRNA; innate immunity; nsp15; viral antagonist proteins

DOI:  https://doi.org/10.1016/j.celrep.2026.117290
J Immunol. 2026 Apr 15. pii: vkag079. [Epub ahead of print]215(4):

Ligation of TLR2, but not of TLR4 or other Toll-like receptors, induces neutrophil extracellular trap formation in humans.

Hugo Tshivuadi Mosha, Vanessa de Carvalho Oliveira, Olga Tatsiy, Abdelaziz Amrani, Patrick P McDonald.

  Neutrophils are usually the first cells recruited to sites of injury or infection where they mount antimicrobial responses, including the release of neutrophil extracellular traps (NETs). Toll-like receptors play a major role in the recognition of pathogen-associated molecular patterns and all but TLR3 are expressed in neutrophils. Numerous studies have reported that LPS can trigger NET formation; in nearly all cases, however, the ligand was not purified enough to target only TLR4. There also exist isolated reports on the ability of other TLRs to induce NETs. Here we comprehensively revisited the issue of TLR-elicited NET generation using ultrapure ligands. We now report that in humans, NETs are only induced following TLR2 ligation whereas engagement of other TLRs is ineffective (despite eliciting other cellular responses). A widely used (but incompletely purified) LPS preparation potently induced NET generation by binding TLR4, TLR2, and possibly other receptors, confirming previous data from other groups. By contrast, murine NETs are formed upon either TLR2 or TLR4 engagement. Mechanistically, TLR2-triggered NET formation is controlled by signaling kinases that are mobilized early (TAK1, MEK, p38 MAPK) or belatedly (Syk, PI3K, PLCγ2); acts through endogenous factors that bind the RAGE receptor; and involves PAD4 as well as endogenous reactive oxygen species, whereas elastase is dispensable. Conversely, we provide evidence that TLR4 negatively regulates NET formation in humans. Our study shows the surprisingly restricted repertoire of TLRs that can elicit NET formation in humans, and further illustrates how this emblematic neutrophil response differs between humans and rodents.

Keywords:  PAD4; Toll-like receptors; extracellular traps; intracellular signaling; reactive oxygen species

DOI:  https://doi.org/10.1093/jimmun/vkag079
Cell Chem Biol. 2026 Apr 21. pii: S2451-9456(26)00108-X. [Epub ahead of print]

NEK7 Cys298 is important for NLRP3 inflammasome and targetable by dimethyl fumarate.

Yandong Zhang, Helena Lindner, Brian So, Zirong Chen, Haoyang Li, Jiashu Xu, Jiahe Wang, Jie Xu, Alexandru M Petre, Mark D Distefano, Gabriel Núñez, Hening Lin.

  Dimethyl fumarate (DMF), a cysteine targeting agent, is clinically used to treat multiple sclerosis and psoriasis. However, its precise molecular mechanism remains incompletely understood. Here, we investigated the effects of DMF on NLRP3 inflammasome activation. DMF suppresses NLRP3 inflammasome activity at both the priming and activation steps. Using chemoproteomics, we identified DMF targets in macrophages, including IRAK3/4 and RELA/B involved in the NLRP3 priming step, NEK7 involved in NLRP3 early activation, and GSDMD involved in NLRP3 late activation. To understand how DMF inhibits NLRP3 early activation, we showed that DMF modifies NEK7 Cys298 to disrupt NLRP3-NEK7 interaction and inflammasome activation. Interestingly, NEK7 Cys298 is critical for NLRP3 inflammasome activation. This study provides mechanistic insights into DMF's immunomodulatory effects and suggests that targeting NEK7 Cys298 can be a novel strategy for inflammatory diseases. Our work highlights the utility of DMF to identify functionally important cysteine residues in immune signaling pathways.

Keywords:  NEK7; NLRP3; dimethyl fumarate; inflammasome; innate immunity

DOI:  https://doi.org/10.1016/j.chembiol.2026.03.016
Aging Cell. 2026 May;25(5): e70493

Diminished and Altered Cellular Senescence Response in Delayed Wound Healing of Aging.

Maria Shvedova, Rex Jeya Rajkumar Samdavid Thanapaul, Qiaoling Wang, Grace Haeun Shin, Jannat Dhillon, Daniel Sam Roh.

  The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our investigation demonstrated a significant delay in the closure of full-thickness dorsal skin wounds in aged mice compared to their young counterparts. Analysis of the wound microenvironment revealed a transient upregulation of senescence-associated markers (p16, p21, senescence-associated β-galactosidase) and senescence-associated secretory phenotype factors in the wound tissue of young mice, a response that was markedly attenuated in aged mice. Single-cell RNA sequencing analysis of all cells isolated from day 6 wounds identified a distinct population of p16+/p21+/Ki67- senescent fibroblasts in young mice, characterized by a transcriptional signature indicative of prohealing extracellular matrix production, a finding corroborated in human wound tissue from young donors. Crucially, in aged wounds, we observed a lower quantity of these senescent cells, a deficit compounded by a qualitative, age-dependent shift in their function, moving away from beneficial extracellular matrix remodeling toward a more detrimental pro-inflammatory state, which ultimately can contribute to delayed wound healing.

Keywords:  SASP; aging; mice; p16; p21; senescence; wound healing

DOI:  https://doi.org/10.1111/acel.70493