bims-cediti 2026-07-12 papers

bims-cediti

Biomed News

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

Issue of 2026–07–12
eighteen papers selected by
Kateryna Shkarina, Universität Bonn

The Calcium-Calpain-ALIX Axis is the Major Link Between Gasdermin-D Membrane Pores and Terminal Membrane Damage in Pyroptosis.
Calcium influx through T-type calcium channels regulates secondary necrosis and inflammation through recruitment of ATG9A-mediated membrane repair.
Inhibition of acid sphingomyelinase links sphingolipid remodeling to necroptotic cell death.
Direct visualization of native GSDMD pores reveals lipid-driven stabilization during pyroptosis.
S-phase targeted treatment triggers caspase-dependent lytic immunogenic cell death with pyroptotic features in cancers.
Intracellular structural modifications of natural peptidoglycan fragments preceding NOD2 signaling in mammalian cells.
Sealing and healing: A two-step model for plasma membrane repair.
Phase separation drives NLRP3 inflammasome activation independently of Golgi localization.
Internalized Components of Membrane Attack Complexes Disrupt Proteostasis and Acquire Alarmin-Like Properties.
Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency.
A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury.
Inflammasomes in Intestinal Inflammation: Guardians of Mucosal Homeostasis, Amplifiers of Disease, and Targets for Intervention.
Human Alu loci gain enhancer-type epigenetic modifications in monocytes during response to bacterial LPS.
Malondialdehyde epitopes exposed on dying cells are potent modulators of complement activity and efferocytosis.
Suppression of Lipid Peroxidation by Necrostatins and Their Potential for Dual Targeting of Ferroptosis and Necroptosis.
Nanoscale Organization of Membrane Tension during Neutrophil Extracellular Trap Formation Revealed by Fluorescence Lifetime Imaging.
Independent proviral and antiviral host factors recognize the same capsid protein in divergent human herpesviruses.
DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity.

Res Sq. 2026 Jun 29. pii: rs.3.rs-10100112. [Epub ahead of print]

The Calcium-Calpain-ALIX Axis is the Major Link Between Gasdermin-D Membrane Pores and Terminal Membrane Damage in Pyroptosis.

Gergely Imre, Sylvia Otchere, Himesh Parmar, Kushagra Singh, Lauren Tereshisnki, Natalie Thiex, Adam Hoppe.

Pyroptosis is an inflammatory form of regulated cell death driven by gasdermin-mediated membrane pore formation. Although gasdermin D (GSDMD) pores are widely regarded as the executioners of pyroptosis, recent studies demonstrate that pore formation is not necessarily lethal because cells can actively repair membrane damage through the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. The molecular mechanism that converts reversible GSDMD pore formation into irreversible membrane rupture and cell death remains unknown. Here, we identify a calcium-calpain-ALIX signaling axis that mechanistically links GSDMD pore formation to catastrophic membrane damage. Using primary macrophages, THP-1 monocytes, and HCT-116 epithelial cells, we show that depletion of the ESCRT adaptor ALG-2-interacting protein X (ALIX) abolishes membrane repair, promotes GSDMD accumulation, and markedly increases susceptibility to pyroptotic death. We further demonstrate that GSDMD pores trigger calcium influx, which induces proteolytic cleavage of ALIX. Preventing calcium influx or chelating intracellular calcium blocks ALIX cleavage, reduces GSDMD accumulation, and markedly improves cell survival. Mechanistically, we identify calpains as the calcium-dependent proteases responsible for ALIX cleavage and establish ALIX as a previously unrecognized calpain substrate. Pharmacologic inhibition or genetic depletion of calpains significantly reduces membrane permeabilization and pyroptotic cell death. Mapping of calpain cleavage sites localizes the major cleavage site within the ALIX V-domain. Importantly, calpain-mediated cleavage disrupts ALIX interaction with the ESCRT-III component CHMP4B, thereby preventing ESCRT assembly and membrane repair. In contrast, calcium depletion or calpain knock down restores CHMP4B recruitment and ESCRT activation Collectively, these findings reveal the first mechanistic pathway linking reversible membrane GSDMD pore formation to irreversible membrane rupture. We propose that GSDMD pore-induced Ca2+ influx activates calpains, disables ALIX-dependent ESCRT repair, and drives the transition from repairable membrane injury to terminal pyroptotic lysis. This pathway represents a potential therapeutic target for inflammatory diseases driven by excessive pyroptosis.

DOI: https://doi.org/10.21203/rs.3.rs-10100112/v1
Cell Death Dis. 2026 Jul 08.

Calcium influx through T-type calcium channels regulates secondary necrosis and inflammation through recruitment of ATG9A-mediated membrane repair.

Omar F Audi, Dilara C Ozkocak, Chad Johnson, Bo Shi, Jascinta P Santavanond, Caitlin L Vella, Joanne M Hildebrand, Robyn Sharples, Quan Thinh Le, Lesley Cheng Sim, Amy A Baxter, Mark D Hulett, Ivan K H Poon, Thanh Kha Phan.

Approximately 200-300 billion cells die daily through apoptosis, a prominent form of programmed cell death, to maintain tissue homoeostasis. If apoptotic cells are not efficiently removed by phagocytes, they progress to secondary necrosis when the plasma membrane (PM) becomes permeabilised and release proinflammatory damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP, which drive inflammation and contribute to autoimmune diseases. Thus, controlling inflammation through maintaining PM integrity is critical, however the molecular mechanisms underpinning this is not well defined. Here, we reveal a calcium-dependent process that delays secondary necrosis by promoting PM repair. Mechanistically, calcium influx through T-type voltage-gated calcium channels mediates the recruitment of the lipid scramblase ATG9A and Golgi components to damaged PM regions, thereby preventing early cellular lysis and DAMP release. Inhibition of calcium influx or loss of ATG9A accelerates PM rupture, increases DAMP secretion, and exacerbates inflammatory cell recruitment in vivo. Taken together, this study establishes a novel role for T-type calcium channels and ATG9A in regulating PM repair during apoptosis and highlights their therapeutic potential for controlling unwanted inflammation.

DOI: https://doi.org/10.1038/s41419-026-09070-9
RSC Chem Biol. 2026 Jul 02.

Inhibition of acid sphingomyelinase links sphingolipid remodeling to necroptotic cell death.

Luis Agustin E Pilapil, Shweta Chitkara, G Ekin Atilla-Gokcumen.

Necroptosis is a lytic form of programmed cell death that requires activation of the RIPK1/3-MLKL complex and results in plasma membrane permeabilization. Although the protein components governing necroptosis are well defined, the lipid determinants of this process remain poorly understood. Here, we combined lipidomics, pharmacological perturbations of sphingolipid metabolism and functional assays to identify sphingolipid pathways that contribute to necroptotic cell death. Using a panel of small molecule inhibitors, we found that inhibition of acid sphingomyelinase (ASMase) with ARC39 restored cell viability and membrane integrity during necroptosis without altering canonical necroptotic signaling. Lipidomic analysis revealed that ARC39 treatment prevented ceramide accumulation in necroptosis, linking reduced ceramide levels to decreased membrane permeability. Interestingly, ARC39 treatment did not reduce total cellular levels of phosphorylated MLKL (pMLKL) nor its membrane association, suggesting that the observed decrease in membrane permeability arises downstream of MLKL activation. Instead, our findings support a model in which the reduction of ceramide levels impairs productive membrane interactions by pMLKL. Consistent with this interpretation, genetic knockdown of ASMase similarly resulted in increased cell viability, decreased membrane permeabilization, and decreased ceramide levels during necroptosis, further linking ceramide homeostasis to necroptotic membrane damage. Together, these results indicate that ASMase-derived ceramides are important for efficient MLKL-mediated membrane permeabilization in necroptosis.

DOI: https://doi.org/10.1039/d6cb00087h
Sci Adv. 2026 Jul 10. 12(28): eaee4587

Direct visualization of native GSDMD pores reveals lipid-driven stabilization during pyroptosis.

Shirin Kappelhoff, Michael Holtmannspötter, Stefan L Schaefer, Eleonora G Margheritis, Özgün Doga Asik, Nadine Gehle, Hannah Veit, John S H Danial, Rico Franzkoch, Sebastian Strauss, Jonatan Alvelid, Agnes Koerfer, Christian Eggeling, Olympia E Psathaki, Ralf Jungmann, Rainer Kurre, Gerhard Hummer, Jacob Piehler, Katia Cosentino.

Gasdermin D (GSDMD) executes pyroptosis by forming membrane pores, yet how these structures assemble and are regulated in cells has remained technically inaccessible. We introduce polymer-supported plasma membranes (PSPMs), which preserve native PM properties while providing cytosolic access for nanoscopic imaging. Combining PSPMs with DNA-PAINT super-resolution microscopy, we visualize human and mouse GSDMD nanostructures directly at the PM of pyroptotic cells and uncover species-specific differences in pore size. Quantitative analyses reveal that GSDMD assembles into heterogeneous macromolecular architectures, including ring-shaped structures, which correlate with PM permeabilization. The palmitoylation-deficient C191A mutant retains minor membrane association but fails to form complete rings, indicating that ring assembly, more than membrane binding, determines pore activity. Last, we identify PI(3,4,5)P3 as a key regulator of pore stabilization. Its early increase during pyroptosis promotes growth of large rings, and mutations in PI(3,4,5)P3-interacting residues undermine assembly. These findings define the native architecture of GSDMD pores and reveal lipid-dependent stabilization as a central mechanism regulating pyroptotic membrane permeabilization.

DOI: https://doi.org/10.1126/sciadv.aee4587
Cell Death Differ. 2026 Jul 10.

S-phase targeted treatment triggers caspase-dependent lytic immunogenic cell death with pyroptotic features in cancers.

Rituparna Bhatt, Si En Ong, Dan A Erkes, Katia Maria Xavier Leung, Koyo Kinase, Khai Yee Lim, Alexis Bonfim-Melo, Enaam Alghamdi, Sheena Daignault-Mill, Yoon Lim, Nur Jannah Abdul Rahim, Aditya Gopalakrishnan, Xin Yee Ong, Nicole Lisa Li-Ann Goh, Anastasia Gandini, Martina Proctor, Sharad Kumar, Zhen Zeng, Nikolas K Haass, Mathew Jk Jones, Paul Clarke, Andrew E Aplin, Brian Gabrielli.

Immunogenic cell death (ICD) is a type of cell death that can enhance anti-tumour immune responses of chemotherapies and targeted therapies by releasing DAMPs and cytokines that activate dendritic cells and T cells, thereby engaging the patient's immune system to combat the cancer. Pyroptosis and necroptosis are strongly immunogenic because they release DAMPs and inflammatory signals through pore-forming proteins, whereas apoptosis can be tolerogenic. This immunogenic response is contingent on a functional immune system. Unfortunately, most conventional chemotherapies and many targeted therapies also impair the immune system. Here, we investigated the mechanism by which the tumour-selective treatment of Checkpoint kinase 1 inhibitor (CHK1i) combined with low-dose hydroxyurea (LDHU) promotes ICD and anti-tumour immunity. We show that CHK1i+LDHU induces S-phase arrest and caspase-dependent lytic cell death with features of pyroptosis, including gasdermin E cleavage, but cell death was not dependent solely on gasdermin cleavage. Inhibiting caspases was sufficient to block both tumour cell killing and treatment immunogenicity. The mechanism does not rely on any single caspase or gasdermin, consistent with the contributions from multiple caspase-dependent processes. By contrast, doxorubicin that predominantly triggers apoptosis was less effective at stimulating anti-tumour immune responses despite triggering similar levels of cell death. These findings demonstrate that caspase-dependent lytic cell death with pyroptotic features promotes a more effective stimulus for anti-tumour immunity.

DOI: https://doi.org/10.1038/s41418-026-01808-4
Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2535544123

Intracellular structural modifications of natural peptidoglycan fragments preceding NOD2 signaling in mammalian cells.

Shiliu Feng, Christopher Adamson, Chenyu Li, Evan Wei Long Ng, Yuan Qiao.

  Bacterial peptidoglycan fragments (PGNs) are pathogen-associated molecular patterns that activate the mammalian innate immune system, particularly through NOD2 signaling pathways. Since NOD2 is a cytosolic sensor in mammalian cells, cellular assays are commonly used to identify bioactive PGNs that elicit NOD2 response, with muramyl dipeptide (MDP) long recognized as the minimal NOD2 agonist. However, recent studies have highlighted the intracellular phosphorylation of MDP by mammalian N-acetylglucosamine kinase (NAGK) as a critical prerequisite for NOD2 activation, emphasizing the need for further investigation into other host-mediated processing of PGNs. In this study, we examined how various bacterial PGNs, differing in saccharide and stem peptide length, undergo intracellular structural modifications within mammalian cells. Our findings show that disaccharide PGNs are processed through intracellular glycosidic cleavage to generate monosaccharide MurNAc-containing PGNs intracellularly, followed by NAGK-dependent phosphorylation, uncovering an additional essential step that precedes NOD2 activation. To identify the glycosidase responsible for disaccharide PGN cleavage, we provide biochemical and cellular observations that human O-GlcNAcase functions as a promiscuous glycosidase capable of processing certain disaccharide PGNs and potentially modulate their NOD2 activation. Furthermore, we demonstrate that PGNs with a lysine-type tripeptide stem are specifically cleaved into dipeptides and that phosphorylated PGNs are subjected to dephosphorylation in mammalian cells. Together, these findings offer insights into the metabolism and intracellular processing of PGNs in mammalian cells, which are crucial in shaping the host innate immune responses.

Keywords:  LC–MS analysis; NOD2 signaling; intracellular processing; peptidoglycan fragments

DOI:  https://doi.org/10.1073/pnas.2535544123
Dev Cell. 2026 Jul 08. pii: S1534-5807(26)00236-4. [Epub ahead of print]61(7): 1345-1346

Sealing and healing: A two-step model for plasma membrane repair.

Athanasios Kournoutis, Harald Stenmark.

Plasma membrane damage can cause cell death and is associated with neurodegeneration. In this issue of Developmental Cell, Heffner et al. show that annexin A11 (ANXA11) first plugs membrane lesions, before ESCRT-III is recruited to extrude the damaged patch-a two-step repair mechanism compromised by ALS- and FTD-linked mutations.

DOI: https://doi.org/10.1016/j.devcel.2026.06.011
Cell Death Dis. 2026 Jul 06.

Phase separation drives NLRP3 inflammasome activation independently of Golgi localization.

Yuansen Zhu, Chenchao Wei, Xiang Yin, Bolong Lin, Xiaqiong Wang, Hongbin He, Wei Jiang, Rongbin Zhou.

The NLRP3 inflammasome plays a pivotal role in sterile inflammation and various diseases, yet the mechanisms underlying its activation remain elusive. Previous studies have implicated both NLRP3 Golgi localization and palmitoylation-mediated phase separation in its activation; however, mutations in palmitoylation sites or the FISNA domain's intrinsically disordered region (IDR) concurrently disrupt both processes, hindering delineation of their individual contributions to inflammasome activation. Here, we show that NLRP3 exhibits phase separation and Golgi localization simultaneously during inflammasome activation. The polybasic region and FISNA IDR each mediate both processes, whereas lipid-binding motif deletion abolishes Golgi localization without compromising phase separation or inflammasome activity. Conversely, the C-terminal IDR is essential for phase separation and inflammasome activity but dispensable for Golgi localization. By mechanistically uncoupling these processes, our findings establish that phase separation drives NLRP3 activation independently of Golgi localization, thus redefining the spatial and biophysical paradigm of inflammasome assembly.

DOI: https://doi.org/10.1038/s41419-026-09059-4
bioRxiv. 2026 Jul 03. pii: 2026.07.03.736247. [Epub ahead of print]

Internalized Components of Membrane Attack Complexes Disrupt Proteostasis and Acquire Alarmin-Like Properties.

Guiyu Song, Zihan Ma, Matthew Fan, Liying He, Yulong Lan, Weihao Li, Zhengtao Jiang, Quan Jiang, Dylan P Noone, Andrea Nans, Kamal L Nahas, Mahsa Nouri Barkestani, Shaoxun Wang, Qianxun Wang, Pengwei Ren, Jolin Cheng, Yinuo Zang, Haitian Zhou, Justin Johnson, Clancy Mullan, Xiangyu Gong, Doryen Bubeck, Gilbert Moeckel, Michael Mak, George Tellides, Dan Jane-Wit.

Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-κB. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo , and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-κB -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.

DOI: https://doi.org/10.64898/2026.07.03.736247
bioRxiv. 2026 Jun 30. pii: 2026.06.27.735024. [Epub ahead of print]

Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency.

Tianli Xiao, J Richard Brewer, Maximilian Carlino, Ailin Han, Yamato Takabe, Chia-Yi Lee, Fengrui Zhang, Mi Chen, Holly Nicole Blackburn, Amin H Nassar, Qiankun Wang, Kristen Brennad, Liang Shan, Esen Sefik, Diane S Krause, Richard A Flavell.

Loss of function mutation in the human DPP9 gene causes Hatipoglu syndrome leading to severe inflammasomopathy. A key feature of the disease is pancytopenia and patients require bone marrow transplantation, but the mechanism of cell loss is unclear since Dpp9 mutant mice have normal hematopoiesis, suggesting that a distinct mechanism of disease occurs in humans. Here, we present a model of human DPP9 deficiency leveraging reverse genetics in the MISTRG6 humanized mice. We found that CRISPR editing of human CD34 + hematopoietic stem and progenitor cells (HSPCs) led to very efficient and persistent gene deletion in vivo. Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic. However, DPP9 deletion led to little transcriptional changes suggesting post-transcriptional regulation in human HSPCs. Mechanistically, DPP9 deficiency led to the activation of the CARD8 inflammasome resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death. Thus, our results reveal a unique human mechanism of disease and offer therapeutic insight for this inflammasomopathy.

DOI: https://doi.org/10.64898/2026.06.27.735024
Front Immunol. 2026 ;17 1867920

A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury.

Tian Li, Siyu Huang, Junjun Zhang, Xueer Liu, Lihong Zhu, Yue Li, Runmin Lin, Xiaoxuan Chen, Kangsheng Li, Weiqiang Chen, Jiangtao Sheng.

   Introduction: Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide, producing acute neurological deficits and lasting cognitive impairment. Post-injury neuroinflammation is a principal driver of secondary damage and contributes substantially to TBI-induced cognitive dysfunction (TBI-CD), yet the cell-autonomous mechanisms operating within neurons remain incompletely characterised. The AIM2 inflammasome - a cytosolic sensor of double-stranded DNA that drives pro-inflammatory cytokine release and pyroptosis - has been studied primarily in myeloid cells, and its role within neurons after TBI is unclear.
Methods: Here, using a controlled cortical impact (CCI) mouse model, an in vitro mechanical-injury model, AAV-mediated neuron-specific AIM2 knockdown and a comprehensive set of behavioural and molecular assays, we define a neuron-intrinsic, self-perpetuating GSDMD-mtDNA-AIM2 axis that drives neuronal pyroptosis and cognitive decline after TBI.
Results: CCI triggered acute (24 h) AIM2 inflammasome activation specifically in cortical and hippocampal neurons, neuronal pyroptosis and CA3 neuronal loss. AAV-mediated knockdown of AIM2 in hippocampal CA3 neurons significantly reduced neuronal loss in this region and rescued cognitive performance in the Y-maze, novel object recognition and Morris water maze at 14 and 28 days post-injury. Mechanistically, mechanical injury caused early (3-6 h) release of mitochondrial DNA (mtDNA) - but not nuclear DNA - into the neuronal cytosol, where it directly activated the AIM2 inflammasome and engaged caspase-1/GSDMD-dependent pyroptosis; ethidium bromide-mediated mtDNA depletion reversed each pyroptotic marker. Within the first 0.5-3 h post-injury, activated GSDMD N-terminal fragments (GSDMD-NT) translocated to mitochondria, disrupted mitochondrial membrane potential (ΔΨm) and promoted further mtDNA leakage; CRISPR knockout of GSDMD, but not of Bax, prevented this injury-induced mitochondrial dysfunction. Delayed pharmacological inhibition of caspase-1 (VX-765 applied 6 h after injury, after the first wave) selectively suppressed a discrete second wave of cytosolic mtDNA release at 9-12 h and attenuated late-phase LDH release, providing direct experimental evidence for a self-perpetuating second wave of mtDNA-driven AIM2 activation.
Conclusion: These findings define a self-perpetuating, neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome-pyroptosis axis as a driver of TBI-CD, and identify neuron-targeted AIM2 silencing as a candidate therapeutic strategy for limiting post-TBI neuroinflammation and cognitive decline.

Keywords:  AIM2 inflammasome; GSDMD; cognitive impairment; mtDNA; traumatic brain injury

DOI:  https://doi.org/10.3389/fimmu.2026.1867920
Intern Med. 2026 Jul 04.

Inflammasomes in Intestinal Inflammation: Guardians of Mucosal Homeostasis, Amplifiers of Disease, and Targets for Intervention.

Hiroshi Nakase, Yuta Shimomori, Hiroki Kurumi.

  The intestinal mucosa is continuously exposed to dietary antigens, commensal microorganisms, and enteric pathogens, thereby depending on innate immune pathways that detect danger without compromising tissue tolerance. Inflammasomes are cytosolic signaling platforms linking microbial- or stress-sensing to caspase activation, interleukin-1 family cytokine maturation, and gasdermin-dependent membrane responses. In the gut, these pathways support epithelial restitution, mucus and antimicrobial secretion, epithelial cell expulsion, and pathogen containment. Nonetheless, these pathways can drive chronic inflammation through sustained interleukin (IL)-1β production, pyroptosis, neutrophil recruitment, and pathogenic adaptive immunity reinforcement. This review synthesizes the current view of how canonical and noncanonical inflammasomes operate in intestinal epithelial and immune cells, with an emphasis on NLR family pyrin domain-containing (NLRP) 3, NLRP6, NLR family CARD domain-containing (NLRC) 4, Absent in melanoma (AIM) 2, and pyrin. We discuss how cell-intrinsic programs intersect with the microbiota, why protective and pathogenic findings coexist, and how human genetics is beginning to define inflammasome-rich subsets of intestinal diseases. Recent retrospective cohort data sharpen the clinical relevance of pyrin biology: among 396 Japanese patients with inflammatory bowel disease unclassified, 60.1% carried Mediterranean fever (MEFV) variants, and colchicine response among evaluable mutation-positive cases reached 84.6%, thus supporting a distinct colchicine-responsive, IL-1β-skewed enterocolitis subset. Finally, biomarkers and therapeutic opportunities are outlined, and unresolved questions most likely to shape precision-medicine approaches for inflammatory bowel disease and related intestinal autoinflammatory syndromes are identified.

Keywords:  Inflammasome; Inflammatory bowel disease; MEFV; NLRP3; Pyrin

DOI:  https://doi.org/10.2169/internalmedicine.7768-26
Epigenetics Chromatin. 2026 Jul 10.

Human Alu loci gain enhancer-type epigenetic modifications in monocytes during response to bacterial LPS.

Yonghao Pan, Kenji Ichiyanagi.

   BACKGROUND: Bacterial lipopolysaccharide (LPS) potently activates innate immunity. Transposable elements (TEs), particularly lineage-specific short interspersed elements (SINEs), have been implicated in immune regulatory evolution, yet their epigenomic roles during immune activation remain unclear.
RESULTS: Here, we reanalyzed published ChIP-seq data for H3K4me1, H3K4me3, and H3K27ac from human monocytes and mouse macrophage-like cells under basal and LPS-stimulated conditions. We identified widespread and dynamic activation of Alu-associated regulatory regions in human monocytes, accounting for around 15% of total enhancer-associated ChIP-seq peaks with and without LPS stimulation. In particular, over one quarter of the Alu-containing H3K4me1 and H3K27ac peaks appeared only after LPS stimulation. The Alu-containing enhancers that appeared in short treatment with LPS linked to many genes involved in the acute immune and inflammatory responses. On the other hand, prolonged LPS stimulation produced stronger chromatin activation at Alu loci that were linked to genes with more dispersed pathway associations, likely reflecting post-stimulation adaptation or tolerance.
CONCLUSIONS: These findings suggest that Alu elements act as regulatory scaffolds that shape the temporal and functional landscape of human immune responses. Our findings suggest that Alu elements, as primate-specific TEs, may contribute to heightened sensitivity to LPS by shaping species-specific enhancer landscapes.

Keywords:  Alu element; Enhancer regulation; Epigenomics; Innate immunity

DOI:  https://doi.org/10.1186/s13072-026-00686-x
J Lipid Res. 2026 Jul 09. pii: S0022-2275(26)00130-6. [Epub ahead of print] 101100

Malondialdehyde epitopes exposed on dying cells are potent modulators of complement activity and efferocytosis.

Nikolina Papac-Milicevic, Frida C Mohlin, Mirlinda Ademi, Valentina Kovacic, Maria Górna, Kristina Djendjinovic, Clara J Busch, David Weismann, Barbara Bartolini Gritti, Lejla Alic, Florentina Porsch, Daryna Katashynska, Laura Lopez Sans, Anna M Blom, Christoph J Binder.

  Multicellular organisms rely on efficient removal of dying cells to maintain tissue homeostasis. However, during severe tissue damage, when clearance mechanisms are overwhelmed, uncleared dying cells expose various danger-associated molecular patterns (DAMPs), such as malondialdehyde (MDA)- epitopes, which further propagate disease-associated sterile inflammation. MDA-epitopes are present on the surface of dying cells and are specifically recognized by several complement proteins, but the precise nature of their membrane exposure nor whether, and how, this interaction contributes to the removal of dead cells is unknown. Here, we demonstrate that MDA-epitopes were detected on the surfaces of dying cells generated by extrinsic or intrinsic triggers of apoptosis, ferroptosis, and necroptosis, and their occurrence was associated with loss of membrane integrity. Moreover, we show that MDA adducts activate the classical complement pathway by directly binding natural IgM antibodies and C1q and regulate the extent of complement activation through MDA-dependent preferential recruitment of the acute-phase variant of C4b-binding protein (C4BP (α6β0)). This MDA-epitope-guided and C4BP-tuned opsonization of dying cells with IgM, C1q, C4b, and C3b modulates their clearance by phagocytes in human and murine in vitro assays. Our findings identify MDA-epitopes as key mediators in recognizing and clearing dying cells, linking oxidative stress to immune activation and tissue homeostasis.

Keywords:  MDA-epitopes; Sterile inflammation; complement system; efferocytosis

DOI:  https://doi.org/10.1016/j.jlr.2026.101100
J Med Chem. 2026 Jul 10.

Suppression of Lipid Peroxidation by Necrostatins and Their Potential for Dual Targeting of Ferroptosis and Necroptosis.

Amr Al-Farhan, Onkar S Nayal, Derek A Pratt.

Necrostatin-1 (Nec-1), a widely used RIPK1 inhibitor and necroptosis probe, also suppresses ferroptosis, complicating distinction between these cell death pathways. Here, we show that the thiohydantoin moiety of Nec-1 reacts with hydroperoxides to form a sulfenic acid intermediate capable of trapping peroxyl radicals and inhibiting the lipid peroxidation (LPO) that drives ferroptosis. To investigate this mechanism, several analogs were synthesized and evaluated in the FENIX cell-free LPO assay. Anti-LPO activity was enhanced by increasing steric bulk or nucleophilicity around the thiocarbonyl, relocating the thiohydantoin methyl group, or introducing a fully conjugated linker between the thiohydantoin and indole rings. The fully conjugated analog of Nec-1 (dsaturated Nec-1 or dsNec-1) was isolated as a stable species from preparative reactions of Nec-1 and a hydroperoxide, suggesting it mediates Nec-1's antiferroptotic effects. Desaturated derivatives were, however, inactive against necroptosis, indicating that the Nec-1 scaffold is unsuitable for dual-pathway inhibitor development.

DOI: https://doi.org/10.1021/acs.jmedchem.6c01496
Nano Lett. 2026 Jul 04.

Nanoscale Organization of Membrane Tension during Neutrophil Extracellular Trap Formation Revealed by Fluorescence Lifetime Imaging.

Jennifer M Mohr, Linda Kartaschew, Juliana Gretz, Sangeetha Shankar, Elsa Neubert, Sebastian Jung, Sebastian Kruss, Luise Erpenbeck.

  Cells generate and respond to mechanical forces across compartments, with the plasma membrane acting as a nanoscale interface for sensing and transmitting tension. How intracellular forces translate into membrane tension during dynamic processes such as neutrophil extracellular trap (NET) formation remains unclear. Here, we combine the mechanosensitive fluorescent probe Flipper-TR with fluorescence lifetime imaging microscopy (FLIM) to map spatiotemporal plasma membrane tension changes in living cells. After validation in HeLa and dHL-60 cells under osmotic perturbation, we apply this approach to primary human neutrophils undergoing NETosis. Membrane tension transiently increases during chromatin decondensation and nuclear swelling within 60 min, followed by a marked decrease after membrane rupture. Prior to rupture, tension is spatially heterogeneous, indicating localized nanoscale mechanical regulation. Cholesterol depletion abolishes the transient increase and reduces heterogeneity without affecting NETosis kinetics. These findings establish the plasma membrane as a dynamic nanoscale reporter of intracellular mechanical stress during NETosis.

Keywords:  Lifetime Imaging; Membrane Tension; NETosis; NETs; Neutrophils; TCSPC

DOI:  https://doi.org/10.1021/acs.nanolett.6c02099
PLoS Pathog. 2026 Jul;22(7): e1014376

Independent proviral and antiviral host factors recognize the same capsid protein in divergent human herpesviruses.

Yiqi Zhao, Sarah Probert, Jan Birkel, Xin Liu, Yaling Shi, Olivia Shulan Yang, Kangyan Zhao, Yongxu Lu, Geoffrey L Smith.

Intrinsic cellular factors that inhibit herpesvirus infection remain incompletely defined. Here, we identify TRIM5α as a restriction factor for herpes simplex virus type 1 (HSV-1). TRIM5α-mediated restriction requires its ubiquitin ligase activity, PRY-SPRY domain, and the ability to oligomerize. Mechanistically, we show that TRIM5α directly engages capsid protein VP19C and promotes the stability of the VP19C-VP23 complex and its nuclear accumulation. VP19C also activates NF-κB synergistically with TRIM5α and independently. HSV-1 counteracts this host defense by triggering proteasome-dependent TRIM5α degradation. In addition, we show that Cyclophilin A (CypA), which is incorporated into HSV-1 virions, also binds to VP19C, but enhances infection. As with HIV-1 and orthopoxviruses, the proviral activity of CypA is disrupted by cyclosporin A (CsA), but unlike the situation with these other viruses, the proviral activity of CypA is independent of TRIM5α. Notably, CsA and its non-immunosuppressive derivatives also exhibit anti-HSV-1 activity in neuronal cell lines, suggesting a potential therapy for HSV-1 encephalitis. TRIM5α and CypA also interact with orthologs of VP19C in other alpha, beta and gamma human herpesviruses. These findings reveal two distinct host pathways acting on the herpesvirus capsid and provide a foundation for comparing how TRIM5α and CypA modulate infection of unrelated virus families, offering new directions to identify shared principles of host recognition and viral evasion.

DOI: https://doi.org/10.1371/journal.ppat.1014376
bioRxiv. 2026 Jul 02. pii: 2026.06.30.735609. [Epub ahead of print]

DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity.

J Richard Brewer, Ailin Han, Amin H Nassar, Elias Bou Farhat, Holly N Blackburn, Tianli Xiao, Haris Mirza, Walter K Mowel, Esen Sefik, Saskia Hartner, Michael Chiorazzi, Takeshi Ito, Min-Hee Oh, Matthew Z Madden, Athreya Rangavajhula, Elio Adib, Mustafa J Saleh, Marc Machaalani, Mehrdad Rakaee, Masoud Tafavvoghi, Claire Quattropani, Nicole Gazetos, David Gerber, Farjana Fattah, Jeffrey A SoRelle, Dominic Choo, Mitchell S von Itzstein, Shannon Bevans-Fonti, Mohammad Ghanbar, Karthik Suresh, Thomas Mazumder, Chun J Ye, Toni K Choueiri, Alexander Gusev, Richard A Flavell.

Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFNγ-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.

DOI: https://doi.org/10.64898/2026.06.30.735609