Inflammation
Abstract
Type 2 (T2) inflammation is a defining feature of asthma and associated with epithelial dysfunction, including goblet cell metaplasia and ciliary loss. Here, we investigated whether T2 inflammation and associated 15 lipoxygenase-1 (15LO1) activity alters mitochondrial metabolism in airway epithelial cells (AECs) and contributes to disease pathophysiology. Freshly isolated AECs from T2-high asthmatic participants exhibited increased oxygen consumption rates (OCR), including elevated basal respiration and proton leak, alongside reduced coupling efficiency compared to T2-low participants. These functional changes were accompanied by increased expression of electron transport chain (ETC) proteins, worse lung function and epithelial phenotypic changes. In vitro, IL-13 stimulation of differentiated AECs recapitulated these findings, inducing higher OCR, increased ETC protein levels, and enhanced proton leak while paradoxically reducing intracellular ATP. These metabolic alterations are associated with increased uncoupling protein 2 (UCP2) expression and goblet cell differentiation. Mechanistically, 15LO1 emerged as a key regulator, as ALOX15 knockdown or pharmacologic inhibition reduced OCR parameters, ETC protein expression, UCP2, and goblet cell markers, without effect on ATP levels, suggesting additional regulatory mechanisms. Collectively, these findings identify a metabolic axis linking T2 inflammation, mitochondrial dysfunction, and airway epithelial metabolism, while highlighting 15LO1-driven mitochondrial uncoupling as a potential therapeutic target in asthma.
Authors
Xiuxia Zhou, Krithika S. Rao, Sruti Shiva, Catharina van Heusden, Qi Wei, Nobuhiko Fukuda, Mayoko Tsuji, Angelina Kendi, Laura R. Bradley, Jinming Zhao, John B. Trudeau, Anuradha Ray, Richard C. Boucher, Sally E. Wenzel
Abstract
Authors
Miki Kamiyama, Jingjing Shi, Lorna Rinck, Yanzhu Lin, Yifang Mao, Xiaowen Zhang, Ashik Ahmed Abdul Pari, Stephanie F. Preuss, Marlene Hoffarth, Gladys Hofsetz, Yuxi Di, Asmaa Zahran, Carleen Spegg, Maria Riedel, Donato Inverso, Roxana Ola, Junhao Hu, Kari Alitalo, Hellmut G. Augustin, Mahak Singhal
Abstract
Familial Episodic Pain Syndrome (FEPS) is a rare inherited disorder characterized by recurrent episodes of severe upper-body pain triggered by stimuli such as cold, stress, or fasting. A gain-of-function mutation (N855S) in the Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel has been identified in affected individuals, yet the cellular mechanisms driving FEPS pain remain poorly defined. Although TRPA1 has been primarily studied in sensory neurons, emerging evidence suggests that non-neuronal cells may contribute to pain signaling. To define the cell-specific role of mutant TRPA1 (TRPA1mut), we generated mouse models selectively expressing TRPA1mut in Schwann cells or sensory neurons, using CRISPR-based and Cre-loxP strategies. Patch-clamp recordings confirmed enhanced agonist-evoked currents in TRPA1mut compared with wild-type channels. Behavioral analyses revealed that neuronal TRPA1mut mediates acute nociceptive responses, whereas Schwann cell TRPA1mut drives mechanical allodynia induced by subthreshold TRPA1 agonists and physiological triggers relevant to FEPS, including fasting, cold exposure, and restraint stress. These responses were associated with increased reactive oxygen species and accumulation of 4-hydroxynonenal in sciatic nerves and were attenuated by antioxidant treatment. These findings uncover a previously unrecognized Schwann cell-dependent mechanism of TRPA1-driven pain and identify non-neuronal TRPA1 signaling as a potential therapeutic target in FEPS and related pain channelopathies.
Authors
Matilde Marini, Martina Chieca, Elisabetta Coppi, Marco Montini, Lorenzo Bonacchi, Lorenzo Landini, Irene Scuffi, Kelvin Y. Kwan, Alice Papini, Gaetano De Siena, Elisa Bellantoni, Lucrezia Timotei, Elena Colzi, Valentina Albanese, Gabriele Ferroni, Evelynn D. N. Melo, Marie-Christine Birling, Romain Lorentz, Romina Nassini, Francesco De Logu
Receptor-tuned Interleukin-2 Mutein Decouples Treg Expansion from ILC2-driven Cutaneous Inflammation
Abstract
Low-dose interleukin-2 (IL-2) and IL-2 muteins are being developed to expand regulatory T cells (Tregs) for autoimmune disease therapy, but injection site reactions (ISRs) remain frequent and poorly understood. Here we show IL2Mut24, a murine surrogate of IL-2 receptor α (IL-2Rα, CD25)-biased IL-2 mutein, enhances Treg expansion yet paradoxically exacerbates cutaneous inflammation compared to wild-type IL-2. Using immunodeficient mice, antibody blockade and adoptive transfer, we identify group 2 innate lymphoid cells (ILC2s) as key drivers of IL-2-induced skin inflammation, defining a CD25-dependent innate activation axis that constrains immune tolerance. In cynomolgus monkeys, the CD25-biased IL-2 mutein efavaleukin alfa promotes greater peripheral Treg expansion than aldesleukin (recombinant human IL-2) but is accompanied by transient increases in IL-5 and dose-dependent ISRs, indicating conservation of this innate inflammatory program across species. To improve the therapeutic window, we engineer receptor clamps by linking IL2Mut24 to antibodies against CD25 to restrict IL-2 access to CD25. This receptor-tuned IL-2 preserves Treg selectivity, suppresses ISRs, and outperforms IL2Mut24 in experimental autoimmune encephalomyelitis by restraining Th17 responses. These findings reveal a conserved innate mechanism underlying IL-2–associated toxicity and establish receptor-tuning as a strategy to improve the safety and efficacy of IL-2–based immunotherapy.
Authors
Anupama Sahoo, Cody Moorman, Mina Tsenkova, Yi Jing, Alexis Valdovinos, Xin Luo, Shiping Lu, Songyu Wang, Renee R. Hukkanen, Madeline Fort, Helen S.H. Tang, Ronya Primack, Shweta Mandavalli, Weiwen Deng
Abstract
Receptor activator of NFκB ligand (RANKL) is important for bone metabolism, but also modulates immune processes. We showed that mast cells (MCs) are involved in RANKL regulation, but the importance of MC-derived RANKL in skin inflammation has not yet been investigated. In contact hypersensitivity (CHS), the absence of MC-derived RANKL led to reduced skin inflammation due to impaired leukocyte infiltration and blood lymphopenia. Surprisingly, we observed a massive hyperplasia of the distant inguinal lymph nodes in the absence of MC-RANKL. Using adoptive transfers, flow cytometry and whole-mount 3D imaging, we demonstrated that this was not caused by structural maladaptation, but rather by the inability of lymphocytes to exit in a timely manner. Importantly, RANKL deletion in skin MCs only replicated the effect of LN hyperplasia and blood lymphopenia. Moreover, MCs were involved in serum sphingosine-1-phosphate (S1P) regulation during sensitization and challenge. Intravascular administration of S1P restored timely lymphocyte egress, demonstrating a MC-induced organ-spanning RANKL-S1P axis. Consequently, peripheral skin MC-derived RANKL is essential for the timely lymphocyte egress from distant LNs, which may have important implications for the targeted treatment of inflammatory skin diseases.
Authors
Konstantinos Katsoulis-Dimitriou, Waqar Umer, Laura Knop, Tanja Schickschneit, Aaron Hoffmann, Ali El-Bizri, Lea M. Schmitter, Kathleen Baumgart, Nouria Jantz-Naeem, Vladyslava Dovhan, Charlotte Heidelbach, Lars Philipsen, Andreas J. Müller, Stephan Fricke, Sascha Kahlfuß, Thomas Schüler, Jan Dudeck, Anne Dudeck
Abstract
Multiple sclerosis (MS) is a complex inflammatory disease of the CNS resulting from an intricate interplay between genetic predisposition and environmental factors. Vitamin D (VD) deficiency is one of the established risk factors for MS. CD46 costimulation of CD4+ T cells induces a switch from Th1 to type I regulatory cells (Tr1), characterized by increased IL-10 production. This switch is impaired in MS T cells but can be restored by VD, which also strongly promotes expression of CD226 on CD46-activated T cells. The rs763361 polymorphism in the CD226 gene, resulting in a non-synonymous Gly307Ser variant, is associated with increased risk for MS. Herein, we show that expression of this CD226 risk allele disrupts the ability of CD46-activated T cells to operate the IFNγ/IL-10 switch upon VD exposure. Mechanistically, the risk variant impairs activation of the integrin LFA-1, which promotes the Tr1 phenotype. LFA-1-mediated Tr1 differentiation is also impaired in MS T cells expressing the CD226 risk allele upon CD46 and VD stimulation. Our study unveils how, in the context of MS susceptibility, a genetic polymorphism and an environmental factor act in concert to control the differentiation of Tr1 cells.
Authors
Saniya Kari, Aymeline Debonlier, Thibault Angles, Beatriz Chaves, Charles Grosjean, Florence Bucciarelli, Valérie Duplan-Eche, Lucie Nozeran, Jessica Lavery, Elena Morandi, Beatrice Pignolet, Max Mimpen, Joost Smolders, Roland Liblau, Abdelhadi Saoudi, Jan Damoiseaux, Frederick Masson, Loïc Dupré, Anne L. Astier
Abstract
Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral anti-inflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In two glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing (snRNA-seq) and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell (iPSC)–derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.
Authors
Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J. Gill, Peter Canoll, Jeffrey N. Bruce
Abstract
Dietary cholesterol and de novo cholesterol synthesis in the liver use reciprocal coordination to maintain cholesterol homeostasis. However, high level of dietary cholesterol still promotes excessive cholesterol accumulation in the liver, leading to metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms remain poorly understood. Here we show that hepatic S100A11, a member of the S100 family of calcium-binding proteins, positively responds to the dietary cholesterol level and is involved in hepatic cholesterol metabolism. S100A11 localizes to the endoplasmic reticulum and can bind to cholesterol. In vivo and in vitro, hepatic overexpression of S100A11 led to SREBP2 activation to promote cholesterol synthesis, uptake, and accumulation, consequently exacerbating steatohepatitis. In contrast, inactivation of S100A11 had opposite effects and improved steatohepatitis. Mechanistically, S100A11 triggers the non-canonical entry of SREBP2 into the nucleus through a S100A11-ANXA1-KPNB axis, distinct from the well-known INSIG-SCAP pathway or Caspase2 pathways. Therefore, our work identifies S100A11 as a regulator of liver cholesterol metabolism, providing a promising target to treat MASH and hypercholesterolemia.
Authors
Mingfeng Zhan, Xiumei Xu, Huiyin Wu, Qijing Fan, Hongsheng Lu, Chengbin Li, Linqiang Zhang, Tingting Zhu, Yunqian Shen, Jing Liu, Yaomei He, Yingjie Wu, Jingjing Zhang, Xiaoju Zou, Bin Liang
Abstract
Regulatory T (Treg) cells in visceral adipose tissue (VAT) play essential roles in systemic metabolic homeostasis under distinct physiological and pathological conditions. However, the metabolic cues that drive Treg cell subset specialization in the obese VAT niche remain elusive. Here, we demonstrated that palmitic acid instigated chronic VAT inflammation and systemic metabolic disturbance by compromising the immunosuppressive function of the ICOShi Treg subset. Palmitic acid, but not oleic acid, activated Crebzf expression in VAT Treg cells from HFHS diet-induced obese and ob/ob mice. Crebzf deficiency significantly attenuated diet-induced obesity and inflammation by upregulating the suppressive function of VAT ICOShi Treg cells. Moreover, adoptive transfer of Crebzf-deficient ICOShi Treg cells into Rag1-/- mice alleviated HFHS diet-induced inflammation and metabolic disorders more effectively than transfer of Crebzf-sufficient ICOShi Treg cells. Mechanistically, CREBZF interacted with c-JUN to inhibit Foxp3 activity, thereby impairing the stability and inhibitory cytokine production of ICOShi Treg cells. In human subjects, CREBZF levels in VAT Treg cells were elevated and negatively correlated with FOXP3 activity. Collectively, these findings uncover a specific ICOShi Treg subset that responds to palmitic acid, thereby coupling obesogenic signals to VAT remodeling and systemic metabolic homeostasis.
Authors
Weitong Su, Yuxiao Liu, Xi Yan, Mengyao Huang, Linghao Xu, Jing Lin, Xufeng Chen, Puyuan Hu, Chenlin Gao, Jian Wen, Hongdong Wang, Dong Ding, Zengpeng Zheng, Wenjing Li, Lianjia Li, Zhan Liu, Keyu Qian, Jing Gao, Tingting Zhang, Xiaobing Mao, Haibing Zhang, Wei Lu, Bin Li, Hong Li, Aoyuan Cui, Yan Bi, Chunxiang Zhang, Yu Li
Abstract
Cholesterol overload contributes to metabolic dysfunction–associated steatohepatitis (MASH) progression. One major pathway that limits hepatic cholesterol accumulation is export via VLDL secretion. While sterol regulatory element–binding protein (SREBP) activity is suppressed by insulin-induced gene 1 (INSIG1) under high sterol conditions, VLDL secretion nonetheless persists to prevent lipotoxicity and liver injury, presenting an unresolved paradox in cholesterol sensing and lipoprotein export. Here, we identified a cholesterol-responsive interaction between nuclear factor erythroid 2 related factor-1 (NFE2L1) and INSIG1 that preserved cholesterol homeostasis by sustaining VLDL secretion. Liver-specific NFE2L1 deletion elevated INSIG1 abundance, suppressed SREBP1 activation, and impaired VLDL secretion, leading to hepatic cholesterol accumulation and liver injury. Mechanistically, NFE2L1 bound to INSIG1 via its N-terminal homology box 2 (NHB2) domain; free cholesterol strengthened this interaction to promote INSIG1 degradation, thereby enabling SREBP1 activation and VLDL export. In NFE2L1-deficient mice, WT NFE2L1, but not a mutant NFE2L1 form unable to interact with INSIG1 (NHB2-deleted mutant, ΔNHB2), restored SREBP1 activity and VLDL secretion. Lipidomics analysis revealed that NFE2L1 deficiency reduced serum triglyceride composition, which was restored exclusively by WT NFE2L1. In a murine MASH model, NFE2L1 overexpression activated SREBP1/2, lowered hepatic cholesterol, and attenuated liver injury, inflammation, and fibrosis, without elevating atherogenic lipoproteins owing to compensatory LDL receptor upregulation. Together, these findings explain how VLDL secretion capacity was maintained under cholesterol excess and identify the NFE2L1/INSIG1 axis as a sterol-responsive safeguard for hepatic lipid homeostasis and a potential therapeutic target for MASH.
Authors
Shijun Deng, Jessica E. Freed, Grace Y. Lee, Gizel Askin, Zhe Cao, Özgür Cakici, Bo Yuan, Sheng Tony Hui, Karen E. Inouye, Isabel Graupera, Gökhan S. Hotamışlıgil
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)