bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–06–28
24 papers selected by
Kateryna Shkarina, Universität Bonn
  1. Supramolecular Assemblies Drive Activation of Inflammasomes.
  2. Threat assessment shapes neutrophil cell fate upon inflammasome activation.
  3. Theme and variations: activation and regulation of gasdermin-mediated inflammation.
  4. Induced pluripotent stem cell-derived macrophages enable broad modeling of human inflammasome signaling.
  5. Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload.
  6. Lysosomal ion homeostasis drives delayed hair cell death after aminoglycoside uptake.
  7. Mrgpra2+ neutrophils stand guard in the infected bone marrow.
  8. C-terminal lysine residues localise NLRP10 at lipid droplets and govern NLRP10 oligomer formation.
  9. Necroptotic cell death and immunomodulator release induced by T-cell engaging anti-lymphoma therapies.
  10. Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.
  11. AKT-mediated phosphorylation of ZDHHC5 promotes NOD1 palmitoylation and innate immune signaling.
  12. The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
  13. The metabolic basis of regulated cell death.
  14. Iron drives protease-independent cleavage of gasdermin D in allergic airway diseases.
  15. A genetic screen identifies O-antigen as essential for Rickettsia parkeri survival in macrophages by protecting from inflammasomes and interferon-stimulated genes.
  16. NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice.
  17. Diverse infection models demonstrate robust resistance of Mycobacterium tuberculosis to innate immunity.
  18. Phospholipid Remodeling as a Key Regulator of Ferroptosis.
  19. Lipid droplet-mitochondria tethering releases MAVS inhibition to potentiate antiviral immunity.
  20. Adipocyte caspase-8 but not RIPK3 promotes adiposity.
  21. Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.
  22. NINJ1 plays a vital role in the release of neutrophil extracellular traps during acute lung injury.
  23. Surveying the roles of NINJ1 in plasma membrane rupture.
  24. Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
  1. Adv Exp Med Biol. 2026 ;1514 41-54
    Supramolecular Assemblies Drive Activation of Inflammasomes.
    Zhangfei Shen, Chen Wang, Tian-Min Fu.
      Inflammasomes are large cytosolic protein complexes that detect and respond to pathogenic and endogenous danger signals, triggering critical innate immune defenses. This chapter outlines the structural and mechanistic features of canonical inflammasomes, focusing on NLRP1, NLRP3, NAIP-NLRC4, NLRP6, and AIM2. Canonical inflammasomes often comprise a sensor protein (e.g., an NLR or AIM2), the adaptor ASC, and pro-caspase-1, which are assembled upon ligand binding. NLR sensors detect diverse signals, ranging from bacterial toxins and lipopolysaccharides to crystals and ATP, while AIM2 recognizes cytosolic double-stranded DNA. Once activated, these inflammasomes facilitate caspase-1-dependent maturation of IL-1β and IL-18, as well as cleavage of gasdermin D, culminating in pyroptotic cell death and pro-inflammatory cytokine release. Structural insights reveal that inflammasome activation transitions from an autoinhibited state to filamentous or ring-shaped supramolecular assemblies. Despite ligand diversity and varying activation pathways, inflammasomes share unifying principles in their oligomerization-driven activation. Elucidating these mechanisms advances our understanding of how cells mount rapid, robust immune responses and paves the way for developing therapeutic interventions in inflammatory and infectious diseases.
    Keywords:  AIM2; Caspase; DAMP; GSDMD; Inflammasome; Innate immunity; NAIP; NLR family; NLRC4; NLRP1; NLRP3; NLRP6; Noncanonical inflammasome; PAMP; Pyroptosis
    DOI:  https://doi.org/10.1007/978-3-032-26629-3_3
  2. Sci Adv. 2026 Jun 26. 12(26): eaeb4830
    Threat assessment shapes neutrophil cell fate upon inflammasome activation.
    See Jie Yow, Bing-Chen Wu, Hai Shin Pung, Safwah Nasuha Rosli, Hui Wen Yeap, Ghin Ray Goh, Kay En Low, Isabelle Bonne, Jizhong Shi, Shuizhou Yu, Motomi Osato, Davey Kneafsey, Gabrielle Chappell, Ye Chean Teh, Shu Zhen Chong, Melissa S F Ng, Immanuel Kwok, Jelena S Bezbradica, Dave Boucher, Kaiwen W Chen.
      Inflammasomes are cytosolic multiprotein complexes that activate caspase-1, which promotes inflammation and host defense by driving cytokine maturation and pyroptosis. Several studies reported that caspase-1 selectively drives cytokine maturation without concomitant pyroptosis in neutrophils, yet the molecular mechanisms by which neutrophils resist caspase-1-dependent pyroptosis remain unclear. Here, we report that granulocyte-macrophage colony-stimulating factor (GM-CSF) licenses neutrophil pyroptosis upon NLRP3 and Pyrin activation by amplifying TLR4-driven inflammasome priming. Single priming with the TLR1/2 agonist, Pam3CSK4, was also sufficient to license neutrophils to pyroptosis upon NLRP3 and Pyrin activation, as Pam3CSK4 triggered superior inflammasome priming compared to LPS, the prototypic inflammasome priming agent. We further demonstrate that neutrophil pyroptosis requires autocrine TNFR1 signaling and provides genetic evidence that Ninj1K45Q/K45Q mutation disrupts plasma membrane rupture in pyroptotic neutrophils. In contrast, NLRC4 expression was not further induced by GM-CSF and therefore does not enhance susceptibility to NLRC4-dependent pyroptosis. Collectively, our data demonstrate that the inflammatory environment dictates neutrophil cell fate upon inflammasome activation.
    DOI:  https://doi.org/10.1126/sciadv.aeb4830
  3. Biochem Soc Trans. 2026 Jul 29. 54(7): 831-843
    Theme and variations: activation and regulation of gasdermin-mediated inflammation.
    Eleanor Yeats Rothera, Soyar Horam, Yizeng Hu, Szu-An Lin, Aidan J David, Tsan Sam Xiao.
      Gasdermins are effectors for pyroptosis, a highly inflammatory form of cell death. Mammalian gasdermin (GSDM) family members harbor N-terminal domains (NTDs) that bind membrane phospholipids and assemble oligomeric pores. Their C-terminal domains are regulatory modules, which suppress the cytolytic function of the NTDs under homeostatic conditions, and in several cases mediate the recruitment of proteases that cleave GSDMs following upstream signaling. The initial model for gasdermin activation was that upon protease processing their NTDs localize to the plasma membrane to assemble oligomeric pores and mediate pyroptosis. Emerging evidence suggests fascinating variations of this paradigm. For example, cleavage-independent pyroptotic activities have been reported for several family members that undergo post-translational modifications such as S-acylation, PARylation, oxidation, or phosphorylation. Furthermore, some gasdermins associate with membranes from organelles such as mitochondria, and often play non-pyroptotic roles in cellular physiology. In the present mini-review, we briefly summarize the molecular mechanisms governing the activation of different gasdermin family members, focusing on protease processing as the most well-studied mechanism. This is followed by discussion of two aspects of gasdermin biology. Namely, cleavage-independent pyroptotic activities and the localization of gasdermins at mitochondria and nucleus implicated in pyroptotic and non-pyroptotic functions. The diverse mechanisms of gasdermin activation and regulation in response to different upstream signaling pathways demonstrate the versatility of this conserved family of pore-forming proteins in various aspects of cellular physiology throughout evolution. The pleiotropic functions of gasdermins in inflammatory disorders, antimicrobial defense, antitumor immunity, neurodegenerative disorders etc., suggest fertile ground for exploration of therapeutic avenues.
    Keywords:  gasdermin; inflammation; membrane targeting; post translational modification; protease; pyroptosis
    DOI:  https://doi.org/10.1042/BST20250185
  4. Cell Rep Methods. 2026 Jun 25. pii: S2667-2375(26)00207-9. [Epub ahead of print] 101506
    Induced pluripotent stem cell-derived macrophages enable broad modeling of human inflammasome signaling.
    Chloe M McKee, Melanie Cranston, Emma C McKay, Mohammad Arefian, Thea J Mawhinney, Ben C Collins, Rebecca C Coll.
      Macrophage models are a mainstay of inflammasome research; however, current in vitro models have significant limitations. Here, we generate induced pluripotent stem cell (iPSC)-derived macrophages (iMacs) to study inflammasome signaling and benchmark them with human monocyte-derived macrophages. We confirm that iMacs express high levels of macrophage markers and are highly phagocytic. Proteomic analysis shows iMacs express many inflammasome sensors and related proteins, and iMacs respond to multiple inflammasome stimuli. The NLRP3 inflammasome is strongly activated in iMacs, and nigericin alone activates NLRP3. The non-canonical inflammasome does not require a priming step, and high NAIP/NLRC4 activation is observed in response to needle toxin. Finally, unlike human monocyte-derived macrophages (HMDMs), talabostat activates NLRP1 in iMacs. Therefore, we demonstrate that iMacs are a physiologically relevant and attractive model to study inflammasome signaling.
    Keywords:  CP: immunology; CP: stem cell; IL-1β; NLRC4; NLRP1; NLRP3; caspase-4; induced pluripotent stem cells; inflammasomes; inflammation; innate immunity; macrophages
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101506
  5. Nat Commun. 2026 Jun 24.
    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 identify the NC1-binding site and the key molecular determinants responsible for channel activation. In addition, we explain the insensitivity of mouse TRPM4 to NC1 and pinpoint specific residues that define NC1 specificity for human TRPM4. 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/10.1038/s41467-026-74814-2
  6. bioRxiv. 2026 Jun 14. pii: 2026.06.10.731244. [Epub ahead of print]
    Lysosomal ion homeostasis drives delayed hair cell death after aminoglycoside uptake.
    Francisco A Barros Becker, Ananya Cholkar, Tor H Linbo, David W Raible.
      Aminoglycoside ototoxicity has been widely reported and remains an important public health issue. Unfortunately, the molecular mechanisms of ototoxicity are not well understood. Here, we report the lysosome compartment as the main driver of delayed cell death triggered by aminoglycosides. By labeling early and late endosomes we show that endocytosis is not an significant path of aminoglycoside uptake. Instead, we show that aminoglycosides are delivered to lysosomes primarily through autophagy. Hair cells can be protected from damage by activation of the dual function lysosomal Two-Pore-Channel 2 (TPC2), stimulated by NAADP agonist but not by phosphoinositide PI(3,5,)P2 agonist. These treatments neutralize lysosomal pH. Moreover, luminal pH changes are also accompanied by changes in ferrous iron availability, though classical ferroptosis inhibitors do not prevent a delayed hair cell death. These findings reveal that lysosomal-driven delayed hair cell death is ferroptosis independent, suggesting that toxicity relies on a distinct mechanism that based on the internal conditions of the lysosomal compartment.
    DOI:  https://doi.org/10.64898/2026.06.10.731244
  7. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00641-8. [Epub ahead of print] 117563
    Mrgpra2+ neutrophils stand guard in the infected bone marrow.
    Guido Wabnitz.
      Zhang and colleagues identify a Mrgpra2⁺ neutrophil subset that deploys neutrophil extracellular traps (NETs) in infected bone marrow. NET release requires coincident defensin and TNF-α signaling, a combination that defines a dual-signal mechanism for context-specific antimicrobial defense during osteomyelitis.
    DOI:  https://doi.org/10.1016/j.celrep.2026.117563
  8. EMBO Rep. 2026 Jun 26.
    C-terminal lysine residues localise NLRP10 at lipid droplets and govern NLRP10 oligomer formation.
    Timo-Daniel Voss, Christoph Winterberg, Adrian Beck, Clarissa Gottschild, Leonie Mueller, Selina M Enayat, Matthias Geyer, Thomas A Kufer.
      NLRP10 is an atypical member of the NLR family because it lacks a leucine-rich repeat domain at its C-terminus. Here, we show that in human epithelial cells and keratinocytes NLRP10 oligomerises in response to m-3M3FBS and SC-10 treatment. NLRP10 co-localises with ASC upon overexpression, but ASC nucleation and recruitment are different to NLRP3. While neither ATP hydrolysis nor the pyrin domain is required, the C-terminal tail region is both necessary and sufficient for oligomerisation. The generation of chimeric proteins shows that the tail region of human and mouse NLRP10 has a conserved function in oligomerisation but determines different protein stabilities. Changes in the subcellular localisation of NLRP10 and oligomerisation are dependent on the presence of evolutionarily conserved lysine residues in the tail region, which localise the majority of NLRP10 to lipid droplets. Our study identifies the C-terminal basic tail of NLRP10 as a key regulatory element for oligomerisation and localisation at lipid interfaces. These findings underline differences in NLRP10 activation with respect to other inflammasome-forming NLRPs and suggest a role of lipids in NLRP10 activation.
    DOI:  https://doi.org/10.1038/s44319-026-00839-9
  9. Cell Death Dis. 2026 Jun 25.
    Necroptotic cell death and immunomodulator release induced by T-cell engaging anti-lymphoma therapies.
    Demi Both, José Saura-Esteller, Anne Martens, Joanne Rietveld, Ingrid Derks, Morris Mes, Jan Willem Duitman, Anita Grootemaat, Nicole van der Wel, Arnon Kater, Marco Haselager, Eric Eldering.
      Autologous cellular immunotherapies, which rely on cytotoxic T lymphocytes (CTLs), are increasingly applied in different B-cell malignancies. The general assumption is that CTLs exert their cytolytic function through granzymes that induce apoptosis in the target cell. However, the killing mechanism of immunotherapeutic CTLs is not clearly elucidated. Using T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells we assessed which cell death pathways were activated in B cell line models as well as in primary material from CLL patients. We demonstrate that for cytotoxic T-cell killing of malignant B-cells by any of the treatment strategies, caspase activity was not essential. We could also exclude a role for TNF or TRAIL-mediated pathways. Using electron microscopy, CAR T-cell and BsAb-mediated cell death showed a mixed apoptotic/necroptotic phenotype. This was corroborated by knockout and chemical inhibition of the essential necroptosis proteins RIPK1, RIPK3, and MLKL. Necroptotic death of target cells correlated with the release of HMGB1 in the supernatant as well as various immunomodulatory molecules from the T-cells. Besides known immune activators IFN-y, IL-17 and IL-6, also anti-inflammatory IL-10 and IL1-RA were released. Moreover, the quantity of these immunomodulators was differentially affected after application of apoptosis versus necroptosis inhibitors. Together, these data demonstrate that (CAR) T-cell-mediated killing of lymphoma cells has a necroptotic arm which is correlated with modulation of the wider immune response. They imply that manipulation of the apoptotic versus necroptotic balance in immunotherapy could affect engagement of the autologous immune response.
    DOI:  https://doi.org/10.1038/s41419-026-08993-7
  10. Nat Commun. 2026 Jun 25. pii: 5135. [Epub ahead of print]17(1):
    Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.
    Rebecca Casterton, Aitana Martinez-Cotrina, Jodi Barnard, Eleanor Wycherley, Yanling Hu, Rhys Anderson, Sebastien Janel, Jiin Byun, Olivia Houghton, Daniel A Solomon, Juan Alcalde, Frank Lafont, Marc-David Ruepp, Frank Hirth, Bart Tummers, Yong-Yeon Cho, Gian De Nicola, Sarah Mizielinska, Manolis Fanto.
      Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-026-73802-w
  11. Front Immunol. 2026 ;17 1819627
    AKT-mediated phosphorylation of ZDHHC5 promotes NOD1 palmitoylation and innate immune signaling.
    Shaojie Mi, Yue Zhu, Qian Li, Xin Wang, Xuewu Guo, Yali Chen.
       Introduction: Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern recognition receptor that detects bacterial peptidoglycan and initiates innate immune responses through membrane-associated signaling complexes. NOD1 activation depends on ZDHHC5-mediated palmitoylation, which promotes its membrane recruitment. However, whether growth factors and insulin modulate this NOD1 activation remains poorly defined.
    Methods: We investigated the effects of growth factors and insulin on NOD1 signaling using biochemical and cell-based approaches. Protein phosphorylation and interactions were analyzed by immunoblotting, co-immunoprecipitation, and mutagenesis assays. NOD1 palmitoylation, membrane localization, and downstream signaling activities were evaluated following modulation of AKT signaling and ZDHHC5 phosphorylation.
    Results: We found that growth factors and insulin positively regulate NOD1 activation through an AKT-ZDHHC5-NOD1 signaling axis. Mechanistically, AKT directly phosphorylated the palmitoyltransferase ZDHHC5 at Ser345 and Ser380, promoting its retention at the plasma membrane and enhancing its enzymatic activity toward NOD1. AKT-dependent phosphorylation increased NOD1 palmitoylation and membrane recruitment, thereby facilitating activation of downstream innate immune signaling pathways.
    Discussion: These findings identify a previously unrecognized mechanism linking growth factor- and insulin-mediated AKT activation to innate immune signaling. AKT-dependent phosphorylation of ZDHHC5 promotes NOD1 palmitoylation and activation, revealing a positive regulatory axis that integrates metabolic cues with innate immune responses. The AKT-ZDHHC5 pathway may therefore represent a potential target for modulating NOD1- driven inflammatory diseases.
    Keywords:  AKT; NOD1 signaling; ZDHHC5; growth factor signaling; palmitoylation; phosphorylation
    DOI:  https://doi.org/10.3389/fimmu.2026.1819627
  12. Dev Cell. 2026 Jun 25. pii: S1534-5807(26)00198-X. [Epub ahead of print]
    The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
    Catherine M Heffner, Georgina P Starling, Lorian C Straker, Philippa C Hawes, Adrian M Isaacs, Jeremy G Carlton.
      Maintenance of plasma membrane integrity is essential for compartmentalization of the cytosol and for cellular viability. Upon membrane damage, several factors including endosomal sorting complex required for transport-III (ESCRT-III) proteins, annexins, stress granules, lipids, and membrane fusion proteins are mobilized to orchestrate membrane repair. However, whether these factors operate independently or act together is unclear. Here, using human cell lines, we expose temporal differences and interdependencies in the recruitment of ESCRT-III and annexin proteins to sites of plasma membrane damage. We show that annexin proteins are recruited immediately and form a plug at the damage site, restricting membrane permeability. We find that ESCRT-III assembles later and acts to release plug-containing damaged membranes from the cell. Further, frontotemporal dementia (FTD)- and amyotrophic lateral sclerosis (ALS)-associated mutations in the ESCRT-III protein, CHMP2B, and the annexin protein, ANXA11, compromise plasma membrane repair, suggesting that defects in this process may contribute to these pathologies. These data present an integrated "sealing and healing" model of membrane repair.
    Keywords:  ALS; ANXA11; CHMP2B; ESCRT-III; FTD; annexin; membrane repair; pore-forming toxin
    DOI:  https://doi.org/10.1016/j.devcel.2026.05.014
  13. Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]
    The metabolic basis of regulated cell death.
    Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.
      Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.001
  14. Cell. 2026 Jun 26. pii: S0092-8674(26)00653-7. [Epub ahead of print]
    Iron drives protease-independent cleavage of gasdermin D in allergic airway diseases.
    Shuangfeng Chen, Fan Deng, Bo Peng, Lian Liu, Junxian Wang, Fuquan Jin, Jiefang Xu, Dongwu Lin, Wen Chen, Danyan Zhang, Chunyan Yi, Jia Zhang, Shufen Zhong, Lin Zhu, Yuying Huang, Jichao Yang, Ran Wang, Xiaoyu Sun, Yaguang Zhang, Zhiyang Ling, Liyan Ma, Xing Liu, Bing Sun.
      Gasdermin D (GSDMD)-mediated interleukin (IL)-33 secretion by lung epithelial cells initiates airway inflammation upon allergen challenge. How environmental allergens activate GSDMD remains elusive. Here, we demonstrate that exposing epithelial cells to allergens triggers protease-activated receptor 1 (PAR1)-dependent ferritinophagy, elevating intracellular labile iron. This iron pool is essential for noncanonical, protease-independent GSDMD activation. The iron chaperone poly(rC)-binding protein 2 (PCBP2) delivers iron directly to GSDMD, initiating a highly localized Fenton reaction. This generates constrained hydroxyl radicals that cleave GSDMD, releasing the active N-terminal p40 fragment to form pores for IL-33 release. Blocking any step of this iron-GSDMD pathway, via iron chelation or genetic ablation, abolishes IL-33 secretion, prevents group 2 innate lymphoid cell (ILC2) activation, and mitigates allergic airway inflammation and tissue damage in mice. Our findings reveal an unconventional, iron-catalyzed, and protease-independent mechanism for GSDMD activation, offering potential new therapeutic targets for allergic inflammatory diseases.
    Keywords:  PAR1; PCBP2; ferritinophagy; gasdermin D; interlunkin-33; iron metabolism; poly(rC)-binding protein 2; protease-activated receptor 1; type 2 immunity
    DOI:  https://doi.org/10.1016/j.cell.2026.06.004
  15. bioRxiv. 2026 Jun 13. pii: 2026.06.12.731980. [Epub ahead of print]
    A genetic screen identifies O-antigen as essential for Rickettsia parkeri survival in macrophages by protecting from inflammasomes and interferon-stimulated genes.
    Han Sun, Alejandro A Guzman, Thomas P Burke.
      Lipopolysaccharide (LPS) is highly immunostimulatory, yet it is evolutionarily conserved among many obligate intracellular bacteria for unknown reasons. We report a forward genetic screen to identify factors required for survival of the tick-borne obligate cytosolic pathogen Rickettsia parkeri in primary macrophages. The most critical factors were WecA and RmlD, which synthesize O-antigen, the outermost layer of LPS. wecA and rmlD mutants grew at similar rates to wild type bacteria in epithelial cells, yet in macrophages they were targeted by guanylate binding proteins (GBPs) and they hyperactivated inflammasomes. Survival of O-antigen-deficient mutants was restored >1,000-fold in macrophages lacking Caspases-1 and -11, interferon signaling, and nitric oxide production, suggesting a multifaceted role for O-antigen in protecting against innate immunity. O-antigen was essential for causing disease in mice and protected R. parkeri against complement in vitro . Despite O-antigen being known as a major target of antibodies, mice immunized with O-antigen-deficient mutants were protected from a lethal rechallenge, suggesting that protection can be elicited independently of O-antigen-targeting antibodies. Together, these findings help resolve a paradox as to why obligate cytosolic bacteria evolutionarily maintain LPS despite it being immunostimulatory, which is that it serves as a multifunctional shield against innate immunity.
    Significance: Eukaryotic innate immune systems evolved to detect conserved microbial structures as danger signals of infection. Intracellular pathogens, in turn, evolved to hide from innate immunity, yet these mechanisms remain incompletely understood. Here, we performed an unbiased forward genetic screen in macrophages that identified lipopolysaccharide O-antigen as a critical virulence determinant in the tick-borne obligate cytosolic pathogen Rickettsia parkeri . We found that O-antigen shields the bacteria from multiple innate immune defenses, including guanylate-binding proteins, inflammasomes, nitric oxide, and complement. These findings reveal why a highly immunostimulatory molecule such as lipopolysaccharide is maintained by an obligate intracellular pathogen and establish O-antigen as a central determinant of Rickettsia cytosolic survival with implications for vaccine development.
    DOI:  https://doi.org/10.64898/2026.06.12.731980
  16. Sci Adv. 2026 Jun 26. 12(26): eaec9499
    NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice.
    Inés Muela-Zarzuela, Elisabet Alcocer-Gómez, Juan M Suarez-Rivero, Evon Low, Abbas Ishaq, Mikel Azkargorta, Amparo Luque-Sierra, Franz Martin, Félix Elortza, Antonio Astorga-Gamaza, Rosa Antón, Sofía Bali, Joaquin Tamargo-Azpilicueta, Alejandra Guerra-Castellano, Irene Díaz-Moreno, Lukasz A Joachimiak, Javier Oroz, Jesús Ruiz-Cabello, Thomas von Zglinicki, Alberto Sanz, Mario D Cordero.
      The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice-more representative of the effects of pharmacological inhibition-are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec9499
  17. bioRxiv. 2026 Jun 11. pii: 2025.11.20.687493. [Epub ahead of print]
    Diverse infection models demonstrate robust resistance of Mycobacterium tuberculosis to innate immunity.
    Marian R Fairgrieve, Ella C Brydon, Roberto A Chavez, Dmitri I Kotov, Russell E Vance.
      Mycobacterium tuberculosis (Mtb) is a robust activator of innate immunity. However, there is little evidence that innate immune mechanisms control Mtb before the onset of adaptive immunity. Prior work has generally used specific pathogen-free (SPF) mouse models and relatively large infectious doses, which may obscure the capacity of innate immunity to control Mtb. Here, we performed ultra-low dose Mtb infections and found that the initial innate immune response was unable to curb even minimal Mtb infectious doses. Additionally, we primed the immune systems of C57BL/6 mice by co-housing with "pet shop" mice prior to Mtb exposure. Co-housed mice were as susceptible to Mtb infection as SPF mice. To pre-activate innate immunity at the site of Mtb infection more specifically, we also infected the lungs of mice with Legionella pneumophila (Lp) prior to Mtb. Innate immunity alone can clear large doses (>100,000 CFU) of Lp from the lung within a few days. However, priming the mouse lung by pre-infection with Lp only modestly reduced Mtb CFU compared to mice infected with only Mtb, indicating that Mtb can robustly replicate even in the presence of a strong anti-bacterial innate response. We performed single-cell RNA-sequencing on myeloid cells from mice either infected with Mtb alone or mice primed with Lp. We found that Lp priming before Mtb infection induced measurable changes in myeloid cells responding to Mtb, but these changes had little effect on innate control of Mtb. Together, these data demonstrate the robust resistance of Mtb to innate immune clearance under diverse experimental conditions.
    DOI:  https://doi.org/10.1101/2025.11.20.687493
  18. J Lipid Res. 2026 Jun 25. pii: S0022-2275(26)00117-3. [Epub ahead of print] 101091
    Phospholipid Remodeling as a Key Regulator of Ferroptosis.
    Tomoyoshi Shingaki, Junken Aoki, Nozomu Kono.
      Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides in cellular membranes. Cellular susceptibility to ferroptosis is strongly influenced by membrane phospholipid composition, which is dynamically regulated through phospholipid remodeling. Phospholipid remodeling, also known as the Lands' cycle, drives the replacement of fatty acyl chains in phospholipids through the coordinated actions of phospholipases A, acyl-CoA synthetases (ACSLs), and lysophospholipid acyltransferases (LPLATs). Phospholipid remodeling critically influences ferroptosis sensitivity by regulating the balance between phospholipid species containing polyunsaturated fatty acids (PUFAs), which promote lipid peroxidation, and those containing saturated/monounsaturated fatty acids, which confer resistance. Recent studies have identified key remodeling enzymes, including ACSL4 and LPLAT12, as central drivers of ferroptosis through the generation of PUFA-containing phospholipids, while other enzymes suppress ferroptosis by limiting lipid peroxidation or removing oxidized phospholipids. In parallel, specific phospholipid species-including arachidonic acid- and adrenic acid-containing phospholipids, di-PUFA phospholipids, and other oxidizable lipid classes-have emerged as critical contributors to ferroptosis. Collectively, these findings highlight phospholipid remodeling as a central determinant of ferroptosis by shaping the membrane lipid landscape.
    Keywords:  acyl-CoA synthetase; ferroptosis; lysophospholipid acyltransferase; phospholipase A; phospholipid; phospholipid remodeling
    DOI:  https://doi.org/10.1016/j.jlr.2026.101091
  19. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00679-0. [Epub ahead of print]45(7): 117601
    Lipid droplet-mitochondria tethering releases MAVS inhibition to potentiate antiviral immunity.
    Qianwen Peng, Wenbo Liang, Wei Wang, Jie Wang, Qi Wang, Chunyuan Zhao, Mutian Jia, Yue Fu, Chengjiang Gao, Hui Song, Ying Qin, Li Tong, Wei Zhao.
      Mitochondrial antiviral signaling protein (MAVS) forms prion-like aggregates to activate innate immunity against RNA viruses, but the metabolic regulation of MAVS remains poorly understood. Here, we show that viral infection induces the formation of lipid droplets (LDs), which physically interact with mitochondria to promote the assembly of MAVS prion-like aggregates. Mechanistically, the LD-resident protein PLIN3 binds to the mitochondrial fusion protein MFN2, thereby relieving MFN2-mediated inhibition of MAVS and enabling its oligomerization. Furthermore, LD-mitochondria contact sites facilitate fatty acid transfer, sustaining mitochondrial membrane potential required for MAVS signaling. Oleic acid (OA)-enriched diets enhance LD formation and boost antiviral immunity in vivo, while myeloid-specific Seipin (an LD biogenesis regulator) deficiency attenuates MAVS activation and exacerbates viral susceptibility. These findings establish LDs as metabolic platforms that bridge cellular lipid metabolism with innate antiviral defense through organelle crosstalk, suggesting LD induction as a novel therapeutic strategy against viruses.
    Keywords:  CP: immunology; MAVS; Seipin; antiviral immunity; innate immunity; lipid droplet; type I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2026.117601
  20. Cell Death Discov. 2026 Jun 23.
    Adipocyte caspase-8 but not RIPK3 promotes adiposity.
    Carmen K Chan, Rukhsana Aslam, Fan Yang, Arshdeep Panesar, Anne Hakem, Razqallah Hakem, Herbert Y Gaisano, Daniel A Winer, Cynthia T Luk.
      Adipocyte death is a key event in the development of white adipose tissue (WAT) inflammation, a major driver of obesity-associated metabolic dysfunction. Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a recently discovered mode of regulated necrosis. Necroptosis has been implicated in several inflammatory pathologies; however, the role of adipocyte necroptosis in obesity remains unclear. In the present study, we sought to investigate the role of adipocyte RIPK3 in obesity and glucose homeostasis. We demonstrated that necroptotic signalling was upregulated in WAT of mice with diet-induced obesity and was associated with body-mass index in human WAT. We also demonstrated that caspase-8, a central regulator of apoptosis, suppresses adipocyte necroptosis both in vitro and in vivo. Adipocyte-specific deletion of caspase-8 in mice reduced adiposity compared to control mice. This difference was not observed with concomitant global deletion of RIPK3. Furthermore, adipocyte-specific deletion of the RIPK3 receptor-interacting protein homotypic interaction motif (RHIM), which is required for necroptotic induction, did not influence weight gain, adiposity, or glucose homeostasis in mice with diet-induced obesity. Caspase-8 knockdown by siRNA or pharmacological inhibition in 3T3-L1 adipocytes suppressed adipogenesis, which may be independent of adipocyte Ripk3. Collectively, our findings suggest that adipocyte RIPK3 RHIM does not play a critical role in obesity and glucose homeostasis. Alternatively, we provide further evidence that caspase-8 plays an essential role in adipocyte differentiation, offering insight into the molecular mechanisms underlying obesity and metabolic dysfunction.
    DOI:  https://doi.org/10.1038/s41420-026-03201-z
  21. Cell Syst. 2026 Jun 23. pii: S2405-4712(26)00130-4. [Epub ahead of print] 101648
    Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.
    Aoife O'Farrell, Zijian Niu, Arjun Raj.
      Macrophages can remember prior activation and subsequently augment their response to restimulation through trained immunity. However, it remains uncertain how trained immunity phenotypes manifest in individual cells. Here, we leverage highly quantitative single-molecule RNA imaging across 90,857 individual macrophages from 26 human donors to reveal inflammatory response dynamics in trained vs. untrained populations at single-cell resolution. Different inflammatory response genes showed distinct single-cell behavior in trained populations upon restimulation. Although training increased transcription of these response genes early after restimulation, untrained populations eventually "caught up" to the transcriptional output of trained populations, highlighting the importance of sampling timescale when interpreting transcriptional assays of training. Training did not significantly alter the relationship between the transcriptional activation of different genes within the same single cell, and any single cell appeared to be capable of training. Overall, these results revealed gene-specific single-cell transcriptional changes that generate population-wide training phenotypes in macrophages.
    Keywords:  RNA FISH; inflammatory response; innate immune memory; macrophages; single cell; trained immunity
    DOI:  https://doi.org/10.1016/j.cels.2026.101648
  22. Cell Death Dis. 2026 Jun 25.
    NINJ1 plays a vital role in the release of neutrophil extracellular traps during acute lung injury.
    Wen-Jing Zhong, Yu-Biao Liu, Xin-Yu Yang, Meng-Rui Chen, Nan-Shi-Yu Yang, Chen-Yu Zhang, Jian-Bing Xiong, Wei-Feng Tang, Cha-Xiang Guan, Yan-Feng Zhang, Jia-Xi Duan, Yong Zhou.
      Excessive neutrophil extracellular traps (NETs) formation is a significant contributor to acute lung injury (ALI), making its inhibition a novel therapeutic avenue to improve outcomes. In this study, we revealed that a novel pore-forming protein ninjurin-1 (NINJ1) was highly expressed in pro-inflammatory neutrophil subpopulations during ALI, using public single-cell RNA sequencing and hotspot analysis. Furthermore, we demonstrated that the NINJ1 oligomerization was essential for the NET release in neutrophils from both acute respiratory distress syndrome (ARDS) patients and ALI mice. Genetic ablation of Ninj1 in neutrophils abolished NET release, thereby attenuating pulmonary dysfunction and reducing ALI-related lethality. Mechanistically, we found that K45 and N60 are critical for NINJ1 oligomerization and subsequent NET release. In summary, our findings reveal a novel pore-forming protein-mediated mechanism for NET release and highlight NINJ1 as a potential therapeutic target for the treatment of ALI/ARDS.Schematic illustration. The novel pore-forming protein NINJ1 mediates the extrusion of NETs, thereby exacerbating pulmonary injury in ARDS/ALI. K45 and N60 are essential for NINJ1 oligomerization and subsequent NET release.
    DOI:  https://doi.org/10.1038/s41419-026-08995-5
  23. Nat Struct Mol Biol. 2026 Jun 25.
    Surveying the roles of NINJ1 in plasma membrane rupture.
    Ishan Deshpande, Nobuhiko Kayagaki.
      
    DOI:  https://doi.org/10.1038/s41594-026-01834-3
  24. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607
    Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
    Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.
      Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.
    Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2026.117607
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