bims-cediti 2026-02-15 papers

bims-cediti

Biomed News

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

Issue of 2026–02–15
twelve papers selected by
Kateryna Shkarina, Universität Bonn

NLRP11 promotes non-canonical inflammasome activation in human macrophages by enhancing caspase-4 recognition of cytosolic lipopolysaccharide.
Pathogen-Induced Lysosomal Membrane Permeabilization: A Critical Interface Between Host Defense and Cell Death.
Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload.
Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death.
Loss of MLKL impairs abdominal aortic aneurysm development by attenuating smooth muscle cell necroptosis.
Cytoskeletal Prestress Regulates RIG-I-Mediated Innate Immunity.
Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses.
RIPK1 regulates β-cell fate via actions on gene expression and kinase signaling in a mouse model of β-cell self-reactivity.
Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
S1PR1 signaling biases neutrophils toward long-lived low-inflammatory functional states.
Shielded by the dead: how killed bacteria shape the dynamics and evolution of innate immunity.
2'-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity.

bioRxiv. 2026 Feb 04. pii: 2026.02.02.703338. [Epub ahead of print]

NLRP11 promotes non-canonical inflammasome activation in human macrophages by enhancing caspase-4 recognition of cytosolic lipopolysaccharide.

María Luisa Gil-Marqués, Pascal Devant, Jonathan C Kagan, Marcia B Goldberg.

Innate immune detection of Gram-negative bacteria depends on sensing of cytosolic lipopolysaccharide (cLPS) by the non-canonical inflammasome, mediated in humans by NLRP11 and caspase-4 (CASP4). Activation of this pathway in human macrophages triggers gasdermin-D activation and pyroptotic cell death. Although CASP4 directly binds LPS in vitro, additional host factors are required for efficient activation in vivo. Here, we show that NLRP11, a primate-specific pattern recognition receptor, facilitates CASP4 recognition of cLPS and promotes non-canonical inflammasome activation. NLRP11 functions upstream CASP4, forming an ASC-independent complex that requires a conserved CASP4 p20 residue, binds cLPS, and enhances CASP4-dependent LPS recognition. Mutational analyses demonstrate that in human macrophages, in addition to LPS binding and CASP4 catalytic activity, CASP4 interaction with NLRP11 is essential for efficient pyroptosis. Together, these findings establish NLRP11 as a primate-specific determinant that enhances CASP4-mediated cLPS detection and non-canonical inflammasome activation, revealing a mechanism for human-specific regulation of innate immunity.

DOI: https://doi.org/10.64898/2026.02.02.703338
Int J Mol Sci. 2026 Feb 03. pii: 1515. [Epub ahead of print]27(3):

Pathogen-Induced Lysosomal Membrane Permeabilization: A Critical Interface Between Host Defense and Cell Death.

Xiao Liu, Zhan Li, Yuru Hu, Tao Li, Hui Wang.

  During pathogen infection, lysosomes are not only pivotal targets exploited by pathogens to evade host defenses and induce cell death, but also an essential frontline of host protection that restricts infection by degrading invading microbes and repairing membrane damage. A broad spectrum of pathogens-including bacteria, viruses, protozoa, and fungi-can trigger lysosomal membrane permeabilization (LMP), resulting in the leakage of lysosomal contents into the cytosol. The released lysosomal factors can selectively activate distinct cell-death programs, including apoptosis, pyroptosis, ferroptosis, and necroptosis. These cell-death processes may limit pathogen dissemination by eliminating infected cells, yet they can also exacerbate disease through excessive inflammatory responses and tissue injury. In this review, we highlight recent advances and systematically discuss the determinants of lysosomal membrane stability, methods for detecting LMP, and LMP-driven cell-death modalities, and we summarize the mechanisms and consequences of pathogen-induced LMP.

Keywords:  cathepsin; cell death; lysosomal membrane permeabilization; lysosome; pathogen infection

DOI:  https://doi.org/10.3390/ijms27031515
bioRxiv. 2026 Jan 30. pii: 2026.01.28.702369. [Epub ahead of print]

Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload.

Celso M Teixeira-Duarte, Wan Fu, Weizhong Zeng, Jianghuang Wang, Xinzhe Jiang, Ziye Zhao, Qing Zhong, Youxing Jiang.

The small molecule Necrocide 1 (NC1) constitutively activates human TRPM4, triggering Na⁺ influx and leading to necrotic cell death, a process termed Necrosis by Sodium Overload (NECSO). NC1 activation is specific to human TRPM4 and does not affect most of the other mammalian TRPM4 orthologs. Here, we elucidate the molecular mechanism underlying NC1 activation and its species-specific selectivity for human TRPM4 using a combination of single-particle cryo-EM, electrophysiology, and cell death assays. We demonstrate that NC1 functions as a non-competitive surrogate of the endogenous Ca²⁺ ligand - it binds to a pocket within the S1-S4 domain adjacent to the Ca²⁺ site and induces the same conformational changes as those triggered by Ca²⁺. Like Ca²-mediated activation, NC1-induced channel opening also requires membrane PI(4,5)P₂ to stabilize the open state. Through comparative mutagenesis and structural analysis of human and mouse TRPM4, we identify the molecular determinants of NC1 specificity. Our results reveal that the insensitivity of mouse TRPM4 to NC1 arises not from a lack of binding, but from drug-induced conformational changes that destabilize the selectivity filter and inactivate the channel. We identify three critical residues that confer NC1 sensitivity, and their substitution renders mouse TRPM4 responsive to NC1, akin to the human channel. Given the upregulation of TRPM4 in various human cancers, our mechanistic insights into NC1 activation and specificity provide a framework for the potential development of cancer therapeutics targeting TRPM4-mediated necrosis.

DOI: https://doi.org/10.64898/2026.01.28.702369
Cell Rep. 2026 Feb 10. pii: S2211-1247(26)00042-2. [Epub ahead of print]45(2): 116964

Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death.

Koyuki Kawamura, Koya Ono, Eikan Mishima, Osamu Hashizume, Marcus Conrad, Hiroaki Miki, Yosuke Funato.

  Mg2+ is an essential cofactor for numerous enzymes, supporting fundamental cellular processes. The phosphatase of regenerating liver (PRL) protein family, frequently upregulated in cancer, inhibits cyclin M (CNNM) Mg2+ efflux transporters. To elucidate the physiological role of PRL in Mg2+ homeostasis at the cellular level, we employed combined genetic knockout and knockdown approaches. PRL deletion led to marked reduction of intracellular Mg2+ levels and triggered extensive cell death. Transcriptomic analysis revealed activation of the NF-κB pathway, and, accordingly, the genetic deletion of NF-κB p65 subunit abrogated cell death. Similarly, CNNM overexpression triggered intracellular Mg2+ decrease, NF-κB activation, and subsequent cell death. Notably, this form of cell death exhibited characteristic morphological features, including actin-driven fiber-like protrusions, distinguishing it from known cell death modalities. Our findings uncover a distinct mode of NF-κB-dependent cell death triggered by intracellular Mg2+ decrease.

Keywords:  CNNM; CP: cell biology; NF-κB; PRL; actin polymerization; magnesium; regulated cell death

DOI:  https://doi.org/10.1016/j.celrep.2026.116964
Cell Death Dis. 2026 Feb 11.

Loss of MLKL impairs abdominal aortic aneurysm development by attenuating smooth muscle cell necroptosis.

Harshal Nemade, Dennis Mehrkens, Hannah Sophia Lottermoser, Zeynep Ece Yilmaz, Julian Mader, Patrik Schelemei, Felix Ruben Picard, Simon Geißen, Gülsah Fülgen Schwab, Friedrich Felix Hoyer, Henning Guthoff, Alexander Hof, Felix Sebastian Nettersheim, Agapios Sachinidis, Norbert Gerdes, Gerhard Sengle, Holger Winkels, Stefan Baldus, Manolis Pasparakis, Martin Mollenhauer, Matti Adam.

Abdominal aortic aneurysm (AAA) is a life-threatening condition characterized by chronic vascular inflammation and progressive aortic wall deterioration. MLKL-driven necroptosis, a highly inflammatory form of cell death, has been implicated in several cardiovascular pathologies; however, its role in AAA remains incompletely understood. Using the aortic elastase-perfusion model, we investigated the impact of necroptosis deficiency on AAA progression in necroptosis-deficient transgenic mice, including RIPK1 kinase-inactive (Ripk1D138N/D138N), MLKL knockout (Mlkl-/-), and MLKL phospho-deficient (MlklAA) animals. Ultrasound analysis revealed that, compared to WT animals, the necroptosis-deficient animals were protected from aneurysm formation, exhibiting preserved aortic structure, reduced immune cell infiltration, and attenuated extracellular matrix remodeling. Bulk mRNAseq revealed significant downregulation of genes associated with fibrinolysis, immune cell activation/migration, inflammation, complement and coagulation cascades in necroptosis-deficient animals. Bone marrow transplantation experiments demonstrated that MLKL deficiency in smooth muscle cells (SMCs), rather than in myeloid cells, was primarily responsible for the protective phenotype. Furthermore, consistent with previous reports, necroptosis induction in MLKL-expressing human and primary mouse SMCs led to increased secretion of proinflammatory cytokines. Live-cell imaging revealed that necroptotic SMCs promote activation and migration of HL60-differentiated polymorphonuclear neutrophils. Collectively, these findings demonstrate that necroptotic SMC death and resulting leukocyte activation play a causative role in AAA development and suggest that pharmacological inhibition of MLKL may represent a promising treatment strategy for AAA disease.

DOI: https://doi.org/10.1038/s41419-026-08427-4
Biophysica. 2025 Dec;pii: 51. [Epub ahead of print]5(4):

Cytoskeletal Prestress Regulates RIG-I-Mediated Innate Immunity.

Arpan Roy, Sydney Sarver, Jarod Beights, Sean Brennan, Sazid Noor Rabi, Sakib Mohammad, Kyu Young Han, Sabrina Nilufar, Farhan Chowdhury.

  Innate immunity is the body's first line of defense for mounting robust antiviral signaling. However, the role of cytoskeletal prestress, a hallmark of cellular mechanotransduction, in regulating innate immune pathways such as retinoic acid-inducible gene I (RIG-I) signaling remains poorly understood. Herein, we show that cells on soft vs. rigid substrates elicit cytoskeletal prestress-dependent activation of RIG-I signaling, leading to differential type-I interferon (IFN) gene expression. Cells were cultured on soft (0.6 kPa) and stiff (8.5 kPa) substrates to modulate cellular traction and prestress, followed by transfection of Poly(I:C), a synthetic viral dsRNA mimic, to measure the RIG-I-mediated innate immune response. Cells on soft substrates show minimal activation of RIG-I signaling, resulting in low expression of IFN-β1 and other IFN-stimulated genes (ISGs), compared to cells on stiff substrates. We further demonstrate that activation of TANK Binding Kinase 1 (TBK1), a downstream effector of the RIG-I pathway, is inhibited in cells on soft substrates due to the cytoplasmic sequestration of the Yes-associated protein (YAP), a HIPPO pathway effector protein. In contrast, cells on stiffer substrates experienced decreased TBK1 inhibition due to the nuclear localization of YAP and exhibited elevated TBK1 activation and heightened IFN and ISG expressions. Together, we demonstrate that cytoskeletal prestress represents a key biophysical regulator of innate immune signaling.

Keywords:  RIG-I; TBK1; YAP; cytoskeletal prestress; traction

DOI:  https://doi.org/10.3390/biophysica5040051
Mol Cell. 2026 Feb 06. pii: S1097-2765(26)00030-4. [Epub ahead of print]

Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses.

Jie Du, Chaoqun Li, Li Chai, Fabao Zhao, Lin Lv, Zongcheng Yang, Zhiyuan Zhao, Rong Gong, Liu Yang, Meng Wu, Meng Nie, Jihui Jia, Dongwei Kang, Chengjiang Gao, Wei Zhao, Mutian Jia.

  Competition between the host and invading viruses for cellular nutrients determines the outcomes of infectious diseases. Nutrients are increasingly being recognized as regulators that interact with immunological signals, but how immune cells sense specific nutrients to regulate antiviral innate immune responses remains elusive. Here, we establish asparagine (Asn) as an intercellular nutritional checkpoint that is sensed by TANK-binding kinase 1 (TBK1) to drive innate immune responses in human and murine cells. Mechanistically, Asn directly binds to TBK1, which robustly induces TBK1 phase separation and forms liquid-like droplets, promoting TBK1 transautophosphorylation and activation. Moreover, viral infection reduces asparagine synthetase (ASNS) expression to establish an Asn-restricted microenvironment, thereby evading TBK1-triggered host immune defenses. Overall, our results suggest that TBK1 is a natural Asn sensor that links host nutritional homeostasis to antiviral immune responses and reveal that targeting Asn availability is a promising therapeutic strategy for diseases involving dysregulated TBK1 activation.

Keywords:  IFN responses; TBK1; asparagine; phase separation; virus infection

DOI:  https://doi.org/10.1016/j.molcel.2026.01.010
Cell Death Dis. 2026 Feb 12.

RIPK1 regulates β-cell fate via actions on gene expression and kinase signaling in a mouse model of β-cell self-reactivity.

Christopher J Contreras, Noyonika Mukherjee, Arianna Harris-Kawano, Egan G Mather, Nansalmaa Amarsaikhan, Christopher Davis, Christine A Berryhill, Madeline Peyton, Debjyoti Kundu, Kaitlyn A Colglazier, Addison S Miller, Renato C S Branco, Travis S Johnson, Steven P Angus, Sylvaine You, Erica P Cai, Andrew T Templin.

Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic β-cells, insulin insufficiency, and hyperglycemia. Receptor interacting protein kinase 1 (RIPK1) is a multifunctional regulator of cell fate with kinase and scaffolding functions, and we previously identified RIPKs as regulators of β-cell cytotoxicity in vitro. Here we report that Ripk1 expression is increased in islets from aged non-obese diabetic (NOD) mice and β-cells from T1D donors, suggesting that RIPK1 may drive cytokine- and autoimmune-mediated β-cell demise in T1D. Using NIT-1 β-cells derived from NOD mice, we observed that TNFα + IFNγ increases RIPK1 phosphorylation, caspase 3/7 activity, and cell death. In contrast, this cytotoxicity was blocked with small molecule RIPK1 inhibition or in Ripk1 gene-edited (Ripk1Δ) β-cells. Small molecule caspase inhibition studies and co-labeling of caspase 3/7 activation and cell death in single cells revealed protection from caspase-dependent and -independent forms of death in Ripk1Δ cells. RNAseq uncovered differential cell death-, immune-, and identity-related gene expression, and kinome profiling identified changes in MAPK, Eph, JAK, and other kinase activity associated with protection from cell death in RIPK1 deficient β-cells. Furthermore, in vitro co-culture assays and in vivo adoptive transfer experiments revealed that NIT-1 Ripk1Δ cells are protected from autoimmune destruction by splenocytes isolated from diabetic NOD mice. Collectively, our findings indicate that RIPK1 promotes β-cell demise in response to cytokine and autoimmune stress via actions on gene expression and kinase signaling. Therapeutics targeting RIPK1 may provide novel opportunities for the prevention or treatment of autoimmune diabetes.

DOI: https://doi.org/10.1038/s41419-026-08471-0
Nat Cell Biol. 2026 Feb 11.

Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41556-026-01879-y
bioRxiv. 2026 Feb 07. pii: 2026.02.05.703783. [Epub ahead of print]

S1PR1 signaling biases neutrophils toward long-lived low-inflammatory functional states.

Yueh-Chien Lin, Takahiro Seno, Alan Y Hsu, Andreane Cartier, Andrew Kuo, Michel V Levesque, Avishek Ghosh, Ingo Fohmann, Victoria A Blaho, Sylvain Galvani, Reed Crocker, Samuel W Kazer, Jose Ordovas-Montanes, Hongbo R Luo, Timothy Hla.

Initiation and resolution of inflammation are required to restore homeostasis. While neutrophils are classically viewed as short-lived effector cells that initiate inflammation, accumulating evidence suggests they can also contribute to resolution processes. Here, we identify neutrophil state characterized by long in vivo half-life, mitochondrial fitness, and reduced inflammatory output. Using myeloid- and neutrophil-restricted sphingosine 1-phosphate receptor-1 (S1PR1) overexpression mouse models (S1PR1hi), we show that elevated S1PR1 signaling is associated with redistribution of neutrophils from the bone marrow to peripheral tissues under steady-state conditions, without inducing overt inflammation or tissue injury. S1PR1hi neutrophils exhibit reduced turnover in vivo, increased mitochondrial membrane potential and oxidative phosphorylation, and transcriptional programs linked to survival and dampened inflammatory signaling. Despite reduced oxidative burst, these neutrophils retain phagocytic capacity and antibacterial activity. In a model of influenza A virus infection, enhanced neutrophil-intrinsic S1PR1 signaling correlates with reduced lung injury, decreased inflammatory output, and improved survival. Together, these findings support a model in which S1PR1 tunes neutrophil persistence and inflammatory potential, thereby shaping immune responses during infection and tissue repair.

DOI: https://doi.org/10.64898/2026.02.05.703783
bioRxiv. 2026 Feb 06. pii: 2026.02.05.704043. [Epub ahead of print]

Shielded by the dead: how killed bacteria shape the dynamics and evolution of innate immunity.

Stephen P Ellner, Nicolas Buchon, Tobias Dörr, Misha I Kazi, Brian P Lazzaro, Alexander Vladimirsky.

The outcome of an infection is determined by the dynamic interplay between microbial growth and host immunity. During a bacterial infection, bacteria killed by innate immune effectors can accumulate as corpses in the extracelluar space, where they can continue to bind (and thus sequester) immune effectors. The impacts on infection outcomes of continued biochemical activity ("sponginess") by the dead have been generally overlooked in theoretical and empirical studies of within-host disease dynamics. We develop a mechanism-based mathematical model of within-host dynamics that incorporates host microbial sensing, the production of immune effectors, the interaction of those effectors with microbes, and shutdown of the immune response after an infection has been controlled. Corpse sponginess impedes the host's ability to control infection, but at the same time, the rapid mopping up of effectors by bacterial corpses also protects host tissue against autoimmune self-harm from immune effectors still circulating after the infection has been resolved. This dual impact of bacterial sponginess alters the trade-off between damage done by infecting bacteria versus autoimmune damage, consequently shifting the evolutionarily optimal immune activation and shutdown kinetics. Thus, the sponginess of bacterial corpses likely shapes both short-term infection dynamics and the long-term evolution of immune systems.

DOI: https://doi.org/10.64898/2026.02.05.704043
Nat Immunol. 2026 Feb 10.

2'-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity.

Arwaf S Alharbi, Sunil Sapkota, Zhikuan Zhang, Ruitao Jin, Erandi Rupasinghe, W Samantha N Jayasekara, Dingyi Yu, Mary Speir, Lorna Wilkinson-White, Liza Cubeddu, Julia I Ellyard, Refaya Rezwan, Daniel S Wenholz, Alexandra L McAllan, Rui Gao, Le Ying, Rasan M Sathiqu, Hani Hosseini Far, Josiah Bones, Sitong He, Marina R Alexander, Kim A Lennox, Paul J Hertzog, Claudia A Nold-Petry, Cameron R Stewart, Carola G Vinuesa, Mark A Behlke, Umeharu Ohto, Olivier F Laczka, Roland Gamsjaeger, Ben Corry, Toshiyuki Shimizu, Michael P Gantier.

Recognition of RNA fragments by Toll-like receptor 7 (TLR7) and TLR8 helps to initiate the innate immune response against pathogens. An outstanding question is why RNA fragments generated during clearance of apoptotic cells fail to activate TLR7 and TLR8 signaling. Here we show that select 2'-O-methyl (2'-OMe) guanosine RNA fragments, including those derived from host RNAs, function as potent TLR7 and TLR8 antagonists and reduce TLR7 sensing in vivo. Mechanistically, these fragments bind to an antagonistic site on these proteins via their 5'-end 2'-OMe guanosine. These findings indicate that host RNAs evade detection because abundant ribosomal 2'-OMe-modified fragments naturally antagonize TLR7 and TLR8. Crucially, rare TLR7 and TLR8 mutations at this antagonist binding site decrease inhibition by 2'-OMe guanosine RNA fragments, leading to autoimmunity in patients. Collectively, this work redefines TLR7 and TLR8 sensing by introducing 2'-OMe guanosine as a natural immune checkpoint for their activation.

DOI: https://doi.org/10.1038/s41590-026-02429-2