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| Open AccessPancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis
IL-22RA1 is highly expressed on pancreatic islets and absent on immune cells. Here, the authors investigate its role by generating animals that lack IL-22RA1 on beta cells and reveal IL22RA1 signalling is critical for insulin biosynthesis and beta-cell health, evidenced by its regulation of MHC II expression and its suppressive effect on inflammation and cellular stress.
- Haressh Sajiir
- , Kuan Yau Wong
- & Sumaira Z. Hasnain
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Article
| Open AccessGut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction
Here, in a follow-up of a clinical study, the authors show that protein pacing and intermittent fasting improves gut symptomatology and microbial diversity, as well as reduces visceral fat compared to a heart-healthy, calorie-restricted diet matched for overall energy intake and expenditure in free-living humans.
- Alex E. Mohr
- , Karen L. Sweazea
- & Paul J. Arciero
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| Open AccessMemory CD8 T cells are vulnerable to chronic IFN-γ signals but not to CD4 T cell deficiency in MHCII-deficient mice
Memory CD8+ T cells persist poorly in MHCII-deficient mice. Here the authors show that this CD8+ T cell attrition is not caused by a lack of CD4+ T cell help, as previously proposed, but by chronic IFN-γ signals derived from endogenous colonic CD8+ T cells.
- Ruka Setoguchi
- , Tomoya Sengiku
- & Shohei Hori
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Article
| Open AccessVascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation
The molecular basis underlying infection infection-mediated lung pathology is not fully revealed. Here the authors report that SPARCL1 expressed in pulmonary capillary endothelial cells contributes to immune pathology in mouse model via pro-inflammatory macrophage induction, while circulating SPARCL1 levels corelate with COVID-19 lethality.
- Gan Zhao
- , Maria E. Gentile
- & Andrew E. Vaughan
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Article
| Open AccessPretreatment with IL-15 and IL-18 rescues natural killer cells from granzyme B-mediated apoptosis after cryopreservation
Natural killer (NK) cells are assessed for various therapies, but sub-optimal cryopreservation dampens their clinical feasibility. Here the authors show that pretreating human NK cells with IL-15/IL-18 prior to cryopreservation improves NK cell post-thaw viability and functions, potentially via anti-apoptosis gene induction and granzyme B degranulation.
- Abdulla Berjis
- , Deeksha Muthumani
- & Neil C. Sheppard
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Article
| Open AccessThe STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion
It has been previously suggested that STING agonists can improve response to CAR-T therapy. Here the authors report the characterization of the STING agonist IMSA101, showing that STING-induced IL18 secretion enhances CAR-T activity in preclinical cancer models.
- Ugur Uslu
- , Lijun Sun
- & Carl H. June
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Article
| Open AccessA comprehensive genetic map of cytokine responses in Lyme borreliosis
Common genetic variants can affect an individual’s immune response to pathogens. Here, the authors uncover and characterize variants regulating cytokine responses in Lyme Borreliosis in 1,060 patients.
- Javier Botey-Bataller
- , Hedwig D. Vrijmoeth
- & Yang Li
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Article
| Open AccessDupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells
Dupilumab-associated head and neck dermatitis has been described in a subset of patients treated with the IL4R-blocker dupilumab. Here the authors characterise the immune cell composition and single-cell transcriptome in comparison with untreated forms of atopic dermatitis in a small cohort showing increases in IL-22-associated genes.
- Christine Bangert
- , Natalia Alkon
- & Patrick M. Brunner
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Article
| Open AccessA commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response
Faecal microbiome transplant has been shown to be able to reduce Clostridioides difficile infection. Here the authors show that an intestinal commensal protozoan reduces C. difficile infection by inhibiting neutrophil recruitment and affecting arginine-ornithine metabolism.
- Huan Yang
- , Xiaoxiao Wu
- & Bing Gu
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Article
| Open AccessThe IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis
Current animal models of periodontitis are biased towards sample collection from gingival tissue, while other periodontal structures may play similarly important role in the initiation and maintenance of inflammation. Here authors present a model that enables a more comprehensive and longitudinal assessment of periodontal tissues, which points to a pivotal role for the peri-root tissues and an IL-33/ST2 axis in the pathogenesis.
- Anhao Liu
- , Mikihito Hayashi
- & Tomoki Nakashima
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Article
| Open AccessTgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape
Development of hindlimbs and external genitalia share several regulatory factors. Lozovska et al. show that Tgfbr1 controls the response to those factors; embryos lacking Tgfbr1 develop two sets of hindlimbs at the expense of the external genitalia.
- Anastasiia Lozovska
- , Artemis G. Korovesi
- & Moisés Mallo
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Article
| Open AccessMalaria blood stage infection suppresses liver stage infection via host-induced interferons but not hepcidin
Blood and liver stages of malaria parasites can affect each other, but it’s not clear how this may affect live-attenuated whole parasite vaccination. Here the authors show that malaria parasite blood stage infection subdues new infection and vaccination by suppressing growth of its liver stage via host cytokines.
- Hardik Patel
- , Nana K. Minkah
- & Stefan H. I. Kappe
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Article
| Open AccessStructural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency
IL-11 and IL-6 signal by binding gp130. Here, Gardner et al. use cryoEM to discover how IL-11 engages gp130 and co-receptor IL-11Rα. Together with MD simulations, they provide insight into gp130 mutations that cause human immunodeficiencies.
- Scott Gardner
- , Yibo Jin
- & Doryen Bubeck
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Article
| Open AccessHuman cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells
Human cytomegalovirus (HCMV) is a ubiquitous pathogen associated with morbidity and mortality in the immunocompromised or immunonaive context. Here the authors show that HCMV exploits STING signalling and subverts the interferon response to support infection of monocyte derive dendritic cells.
- Bibiana Costa
- , Jennifer Becker
- & Ulrich Kalinke
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Article
| Open AccessIntestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders
Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
- Stephen J. Gaudino
- , Ankita Singh
- & Pawan Kumar
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Article
| Open AccessSingle-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade
Single cell profiling of tissue from patients undergoing therapy has the potential to identify drug-induced immune changes. Here the authors show a skin scRNA-seq study of psoriasis patients treated with an IL-23 inhibitor and characterize changes in cell states during early treatment.
- Luc Francis
- , Daniel McCluskey
- & Satveer K. Mahil
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Article
| Open AccessA cytomegalovirus inflammasome inhibitor reduces proinflammatory cytokine release and pyroptosis
Viruses have evolved specific mechanisms to reduce programmed cell death in order to prolong survival. Here the authors show a mouse cytomegalovirus (MCMV) encoded protein that inhibits pyroptosis, proinflammatory cytokine release and the assembly of inflammasomes.
- Yingqi Deng
- , Eleonore Ostermann
- & Wolfram Brune
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Article
| Open AccessLongitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity
Single cell transcriptomics can reveal at high resolution the body’s response to infection. Here the authors have applied this technology to a longitudinal SARS-CoV-2 infected cohort and identified gene expression changes that may predict disease severity and reveal the underlying molecular mechanisms.
- Quy Xiao Xuan Lin
- , Deepa Rajagopalan
- & Shyam Prabhakar
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| Open AccessTargeted therapies of inflammatory diseases with intracellularly gelated macrophages in mice and rats
Membrane-decorated nanomedicines often suffer from reduced efficacy caused by membrane artefacts during the coating process. Here the authors show that intracellularly gelated macrophages preserve membrane properties, stay stable under ambient temperature, and show therapeutic effects in murine models of joint and lung inflammation.
- Cheng Gao
- , Qingfu Wang
- & Ruibing Wang
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Article
| Open AccessSecreted IgM modulates IL-10 expression in B cells
Il-10-expressing B cells play a pivotal role in immune homeostasis, but little is known about the factors and pathways that affect the development of this heterologous population of regulatory B cells. Here authors show in a mouse model that in embryonic life, soluble IgM restrains the expansion of Il-10-positive B cells, via utilizing FcµR and other putative receptors.
- Shannon Eileen McGettigan
- , Lazaro Emilio Aira
- & Gudrun F. Debes
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Article
| Open Access15-Lipoxygenase promotes resolution of inflammation in lymphedema by controlling Treg cell function through IFN-β
Specialised pro-resolving lipid mediators can reduce inflammatory responses and may be active in lymphedema. Here the authors show that in a mouse model 15-LO derived lipid mediators are reduced during inflammation and that a lack of the 15-LO producing enzyme aggravated disease and addition of 15-LO enzyme or Treg cells reduced disease.
- A. Zamora
- , M. Nougué
- & B. Garmy-Susini
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Article
| Open AccessCullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity
Asthma may be exacerbated by respiratory viral infection, but the cellular and molecular mechanisms are still unclear. Here the authors show, using mouse models of asthma with influenza infection, that asthma-induced cullin5 in alveolar macrophages suppresses IFN-β production to promote neutrophilic inflammation but dampens antiviral immunity.
- Haibo Zhang
- , Keke Xue
- & Lei Sun
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Article
| Open Accessp53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome
Radiation induced gastrointestinal syndrome is a complication of radiotherapy and the tumor suppressor p53 is implicated in protection from gastrointestinal toxicity. Here Wang and colleagues show that p53 protection against radiation-induced gastrointestinal syndrome involves intestinal stem cell function and inhibition of inflammation triggered by radiation via the IL12- p40/MHC-II axis.
- Jianming Wang
- , Chun-Yuan Chang
- & Wenwei Hu
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Article
| Open AccessIL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity
Human natural killer T (NKT) cells have been proposed as a cellular platform for CAR engineering. Here the authors report that IL-12 engineering reprograms CAR-expressing NKT cells to long-lived Th1-polarized cells with potent anti-tumor activity in leukemia and neuroblastoma preclinical models.
- Elisa Landoni
- , Mark G. Woodcock
- & Gianpietro Dotti
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Article
| Open AccessEpithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling
IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.
- Jingyun Quan
- , Xiaoxia Wen
- & Tianwen Lai
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Article
| Open AccessInflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).
- Danfeng Dong
- , Yuzhang Du
- & Dakang Xu
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Article
| Open AccessAmino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19
Here the authors show that elevated serum levels of deaminated amino acid catabolites involved in de novo nucleotide synthesis pathway correlate with later COVID-19 severity. These elevated levels are likely associated with abnormal proliferation of airway and vascular cells in the lung.
- Rae Maeda
- , Natsumi Seki
- & Yuki Sugiura
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Article
| Open AccessActivation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
Idiopathic Pulmonary Fibrosis (IPF) consists of lung inflammation and collagen deposition leading to reduced lung function and non-inducible mouse models are needed. Here the authors show a spontaneous mouse IPF model where Ifngr1-/-Rag2-/- mice show enhanced ILC2 activation and function along with pathology similar to IPF.
- Natsuko Otaki
- , Yasutaka Motomura
- & Kazuyo Moro
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| Open AccessMaternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Treatment of pregnant animals with antibiotics can have unexpected effects on offspring. Here the authors use mouse models to show that antibiotic treatment of mothers leads to changes in ILC2 phenotype in neonatal lungs accompanied by changes in the microbiota and microbiota derived butyrate.
- Haixu Xu
- , Xianfu Yi
- & Jie Zhou
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Article
| Open AccessBacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2
The role of interferon-γ (IFNγ) in anti-viral immunity has been unclear. Here the authors show that bacterial-induced or intranasally administered IFNγ effectively restricts SARS-CoV-2 infection in mice through effects on non-hematopoietic cells.
- Kerry L. Hilligan
- , Sivaranjani Namasivayam
- & Alan Sher
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Article
| Open AccessClonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells
The expansion of cells with TET2 mutations within the blood is associated with increased risk for all-cause mortality, development of leukemia and cardiovascular disease. Here authors show IL1 promotes the clonal expansion TET2 knockout cells, enhancing their self-renewal, promoting their myeloid bias and impairing an IL1 driven loss of methylation at lymphoid and erythroid regulatory elements.
- J. McClatchy
- , R. Strogantsev
- & A. Agarwal
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| Open AccessInterleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling
Paneth cell metaplasia (PCM) typically arises in diseases intrinsic to the gastrointestinal tract; however, whether extra intestinal diseases can trigger PCM and the mechanistic pathway by which PCM develops is unknown. Herein, the authors show in an inducible murine model of chronic myelogenous leukaemia that a systemic inflammatory state can trigger IL-33- mediated IL-9 production that leads to small intestinal remodelling and PCM.
- Chengyin Yuan
- , Aditya Rayasam
- & William R. Drobyski
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Article
| Open AccessStructures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant
Interleukin (IL-)11 is a signaling protein that plays key roles in several human diseases. Here the authors describe structures of IL-11 in complex with its receptors and determine the molecular mechanisms through which a variant of IL-11 inhibits signalling, opening avenues for therapeutic development.
- Riley D. Metcalfe
- , Eric Hanssen
- & Michael D. W. Griffin
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Article
| Open AccessTh17-associated cytokines IL-17 and IL-23 in inflamed skin of Darier disease patients as potential therapeutic targets
The use of IL-17/IL-23 blocking therapy for rare inflammatory skin diseases needs proof of principle data for larger clinical trials. Here the authors show that patients with Darier disease have enhanced Th17 cells and, using IL-17/IL-23 blockers, they show that the immune gene signatures are altered in localised skin biopsies.
- Monika Ettinger
- , Teresa Burner
- & Wolfram Hoetzenecker
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Article
| Open AccessNULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing
Unlocking the blood proteome requires exquisite sensitivity and multiplexing to detect low and high abundance proteins simultaneously. Here the authors describe a 200-plex immunoassay with attomolar sensitivity to detect important low abundance proteins in inflammatory diseases and COVID-19.
- Wei Feng
- , Joanne C. Beer
- & Xiao-Jun Ma
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Article
| Open AccessA transcriptional network governing ceramide homeostasis establishes a cytokine-dependent developmental process
Bioactive small molecules mediate transcription factor functions to control cellular processes. Here, Liao et al. discover that a GATA1-regulated metabolic enzyme controls ceramide homeostasis to commission vital cytokine signaling for erythropoiesis.
- Ruiqi Liao
- , Abiola Babatunde
- & Emery H. Bresnick
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Article
| Open AccessTissue-resident B cells orchestrate macrophage polarisation and function
The function of B cells in peripheral blood and secondary lymphoid organs has long been appreciated but whether and how they contribute to tissue immune homeostasis is lesser known. Non-lymphoid organs harbour tissue-resident B cells that include a substantial population of B-1 cells and promote homeostatic anti-inflammatory macrophage polarization via IL-10, with profound effects on bacterial clearance during local infection.
- Ondrej Suchanek
- , John R. Ferdinand
- & Menna R. Clatworthy
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Article
| Open AccessIL-17 signalling is critical for controlling subcutaneous adipose tissue dynamics and parasite burden during chronic murine Trypanosoma brucei infection
Trypanosome brucei is known to colonise the subcutaneous white adipose tissue and the interaction with the cellular locale could play key roles in pathogenesis and host response. Here the author’s use single cell approaches and in vivo animal models, and show a role for IL-17 in the adipose tissue response and parasite burden in a chronic murine model of infection.
- Matthew C. Sinton
- , Praveena R. G. Chandrasegaran
- & Juan F. Quintana
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Article
| Open AccessEbf3+ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells
CAR cells act as HSC niche cells. Here the authors show that CXCL12 ablation in half CAR cells attracts HSCs from affected CAR cells to intact CAR cells whereas CXCL12 ablation in all CAR cells depletes balanced HSCs producing B cells at high levels.
- Taichi Nakatani
- , Tatsuki Sugiyama
- & Takashi Nagasawa
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Article
| Open AccessBiomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy
Cancer immune therapy utilizing interleukin 15 (Il-15) is hampered by the short half-life and systemic toxic effects of the cytokine. Here authors introduce a biomimetic nanovaccine, in which Il-15 and tumor-associated antigenic peptide/MHC-I complexes are co-anchored to cell membrane vesicles of dendritic cell origin, which elicits antigen-specific T cell response leading to superior anti-tumour effect in syngeneic mouse tumour models.
- Kaiyuan Wang
- , Xuanbo Zhang
- & Jin Sun
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Article
| Open AccessInterferon-γ couples CD8+ T cell avidity and differentiation during infection
Although IFN-γ is known to regulate T cell function and expansion during virus-specific responses, its impact on T cells with varying avidity for antigen remains unclear. Here, the authors demonstrate that IFN-γ promotes the expansion of low-avidity CD8+ T cells during the effector phase, but favours those with high avidity in the memory pool.
- Lion F. K. Uhl
- , Han Cai
- & Audrey Gerard
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Article
| Open AccessA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.
- Sarah E. Garnish
- , Katherine R. Martin
- & Joanne M. Hildebrand
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Article
| Open AccessA Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils
Vaccines that specifically induce immunity against bacterial pathogens are required. Here the authors produce and characterize an intranasal liposomal vaccine against a peptide antigen from Streptococcus pyogenes and show that it induces a strong mucosal IgA response lasting for over one year, and that protection is dependent on cellular immunity mediated through IL-17, macrophages and neutrophils.
- Victoria Ozberk
- , Mehfuz Zaman
- & Manisha Pandey
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Article
| Open AccessCREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients
The mechanistic functions of neutrophils in skin inflammation are not fully understood. Here the authors use human psoriasis samples and a mouse model of skin inflammation to study neutrophils and find a CXCR4hi population of NET-forming, phagocytic neutrophils whose induction depends on the transcription factor CREB1.
- Jiaoling Chen
- , Yaxing Bai
- & Shuai Shao
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Article
| Open AccessEpithelial plasticity and innate immune activation promote lung tissue remodeling following respiratory viral infection
After respiratory viral infection and in fibrotic lung disease, repair and remodeling processes particularly affect airway basal cell (BC) and alveolar epithelial cell populations. Here, using single cell transcriptomics and lineage tracing, the authors characterize this process and define roles for innate immune activation in the regulation of BC fate and alveolar remodeling.
- Andrew K. Beppu
- , Juanjuan Zhao
- & Barry R. Stripp
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Article
| Open AccessA tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury
Mechanisms promoting epithelial regeneration after intestinal injury are poorly understood. Here, authors report that intestinal stem cells produce IL-33 after radiation injury, which induces Paneth cells to produce EGF and promote regeneration.
- Marco Calafiore
- , Ya-Yuan Fu
- & Alan M. Hanash
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Article
| Open AccessAutocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis
IPF is a progressive disease with few inflammatory pathology. Here, using alveolar organoid technology, the authors identified autocrine TGF-β-positive feedback in AT2-lineage cells as a core mechanism of inflammation-independent lung fibrogenesis.
- Yasunori Enomoto
- , Hiroaki Katsura
- & Mitsuru Morimoto
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Article
| Open AccessType-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations
The most appreciated producers of pathogenic type-2 cytokines in asthma are T helper 2 cells and group 2 innate lymphoid cells, however, CD8+ cytotoxic T cells are also capable of secreting these mediators. Authors here show that IL-33, a cytokine that is produced by the inflammatory microenvironment, promotes type-2 cytotoxic T cell development, which is linked to asthma exacerbations.
- Esmee K. van der Ploeg
- , Lisette Krabbendam
- & Ralph Stadhouders
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Article
| Open AccessAntigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting
Targeting solid tumours by chimeric antigen receptor (CAR) T cells require strategies that improve trafficking and effector function of these cells in the immunologically hostile cancer microenvironment. Here, authors show that CAR T cells engineered with incorporation of the CD28 transmembrane domain to the 4-1BB costimulatory domain and a membrane-bound form of IL-12 can achieve efficient anti-tumour activity and promote systemic disease targeting via regional T cell delivery in multi-metastatic disease models.
- Eric Hee Jun Lee
- , John P. Murad
- & Saul J. Priceman