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Targeted 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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| Open Access
Nuclear RPSA senses viral nucleic acids to promote the innate inflammatory response
Innate immune responses are the first line of defence against viral pathogens. Here, Jiang et al show that the nuclear located 40S ribosomal protein SA senses viral nucleic acids to selectively enhance proinflammatory cytokine gene expression through epigenetic modification.
- Yan Jiang
- , Siqi Sun
- & Xuetao Cao
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Interleukin-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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Protective effects of macrophage-specific integrin α5 in myocardial infarction are associated with accentuated angiogenesis
During myocardial infarction, cardiac macrophages expand, become activated and play an important role in cardiac repair and remodelling. Here the authors show that integrin α5 is upregulated in infarct macrophages and contributes to myocardial repair, triggering an angiogenic phenotype and protecting from adverse remodelling.
- Ruoshui Li
- , Bijun Chen
- & Nikolaos G. Frangogiannis
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Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation
The immune suppression required for the resolution of acute inflammation is characterised by molecular and metabolic reprogramming of myeloid cells. Authors here show that the transcription factor ZEB1 is a key mediator of the pathway governing transition from inflammation to immunosuppression via regulating mitochondrial translation in macrophages.
- Marlies Cortés
- , Agnese Brischetto
- & Antonio Postigo
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Peripheral helper-T-cell-derived CXCL13 is a crucial pathogenic factor in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (CD) is a rare and potentially fatal lymphoproliferative disorder. Authors here establish a mouse xenotransplantation model of the “not otherwise specified” subtype of the disease and show that the chemokine CXCL13 plays a pivotal role in the pathogenesis and likely produced by peripheral helper cells, which expand upon engraftment.
- Takuya Harada
- , Yoshikane Kikushige
- & Kazuyuki Yoshizaki
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Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome
Paediatric acute respiratory distress syndrome (pARDS) is associated with significant mortality and morbidity. Here the authors use single cell sequencing of tracheal aspirate samples from children with pARDS and characterise immune phenotypes and associations with infection stage and pathogen.
- Tim Flerlage
- , Jeremy Chase Crawford
- & Paul G. Thomas
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Neutrophil-derived catecholamines mediate negative stress effects on bone
Authors present both preclinical data in mice and clinical data from humans in support of the hypothesis that stress negatively affects bone growth and repair. These effects are mediated by neutrophil-derived catecholamines inhibiting cartilage-to-bone transition via β2-adrenoceptor signaling in chondrocytes.
- Miriam E. A. Tschaffon-Müller
- , Elena Kempter
- & Stefan O. Reber
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Copper intrauterine device increases vaginal concentrations of inflammatory anaerobes and depletes lactobacilli compared to hormonal options in a randomized trial
Here, in a randomized trial, the authors comparatively evaluate the effect of a copper intrauterine device versus other contraceptive options on the vaginal environment after one and six consecutive months of use, finding to exert changes on the vaginal microbiota that may potentially lead to detrimental sex and reproductive health.
- Bryan P. Brown
- , Colin Feng
- & Heather B. Jaspan
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Locally organised and activated Fth1hi neutrophils aggravate inflammation of acute lung injury in an IL-10-dependent manner
Acute respiratory distress syndrome (ARDS) is an acute pulmonary disease involving neutrophils. Here the authors characterise lung neutrophil infiltration during ARDS and show that there are neutrophils with different function and transcriptional profile which are regulated by IL-10.
- Kun Wang
- , Muyun Wang
- & Wei Gao
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Article
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CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (iMCD) is a life-threatening inflammatory disease requiring immediate intervention, for which the recommended first-line therapy is the Interleukin-6 pathway inhibitor siltuximab. Authors here show that the change in levels of the chemokine CXCL13 shortly following the start of siltuximab treatment is predictive of response.
- Sheila K. Pierson
- , Laura Katz
- & David C. Fajgenbaum
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Article
| Open Access
Neutrophil breaching of the blood vessel pericyte layer during diapedesis requires mast cell-derived IL-17A
The blood vessel wall is a complex multi-layered structure, yet upon injury or infection, neutrophil leukocytes are rapidly migrating from the blood stream to the affected tissues, by a process termed diapedesis. Authors here show that the final steps of diapedesis through the outer pericyte layer is regulated by perivascular mast cells via IL-17A production.
- Régis Joulia
- , Idaira María Guerrero-Fonseca
- & Mathieu-Benoit Voisin
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RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth
IL-6 and RasGRP1 have been shown to have important functions during inflammation and cancer. Here the authors propose the protein and mRNA of RasGRP1 have opposing functions by promoting IL-6 mediated acute inflammation and inhibiting inflammation-associated cancer through mRNA and protein mechanisms respectively.
- Cong Wang
- , Xue Li
- & Songqing Tang
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Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of cell death pathways during embryogenesis and in infection/inflammation. Here authors show that tyrosine phosphorylation of RIPK1 by upstream kinases limits systemic inflammation and regulates haematopoietic homeostasis.
- Hailin Tu
- , Weihang Xiong
- & Xin Lin
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Epithelial coxsackievirus adenovirus receptor promotes house dust mite-induced lung inflammation
The epithelial protein Coxsackievirus Adenovirus Receptor (CAR) is a virus receptor but may have other functions. Here the authors show that deletion of CAR in mice leads to reduced house dust mite-induced lung inflammation, reduced neutrophil accumulation and alterations in airway remodelling.
- Elena Ortiz-Zapater
- , Dustin C. Bagley
- & Maddy Parsons
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Pneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis
Pneumococcal infection of the cerebrospinal fluid results in bacterial lysis, the release of toxic factors and induction of neuroinflammation. Here, the authors show that the virulence factor pneumolysin enhances the neuroinflammatory response to Streptococcus pneumoniae by the enhancement of endocytosis.
- Sabrina Hupp
- , Christina Förtsch
- & Asparouh I. Iliev
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Human acute inflammatory recovery is defined by co-regulatory dynamics of white blood cell and platelet populations
Inflammation is a protective response of the body. Here, authors show that healthy inflammation induces remarkably consistent changes in white cell and platelet populations, regardless of the underlying cause, including heart attack, infection and trauma.
- Brody H. Foy
- , Thoralf M. Sundt
- & John M. Higgins
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Calcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice
Calcium/calmodulin-dependent protein kinase IV (CaMK4) has been shown to be involved in autoimmunity but it is not clear how it functions in psoriasis. Here the authors show that CaMK4 is increased in psoriasis and promotes inflammatory responses in mouse models of psoriasis mediated through macrophages and keratinocytes.
- Liang Yong
- , Yafen Yu
- & Liangdan Sun
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| Open Access
Hypocrates is a genetically encoded fluorescent biosensor for (pseudo)hypohalous acids and their derivatives
There are a lack of tools to study the dynamics of (pseudo)hypohalous acids in live cells. Here the authors report a genetically encoded fluorescent biosensor, Hypocrates, for (pseudo)hypohalous acids and their derivatives which they use in cells and in a zebrafish tail fin injury model.
- Alexander I. Kostyuk
- , Maria-Armineh Tossounian
- & Vsevolod V. Belousov
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Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors
Loss of function polymorphisms of phospholipase D3 and D4 are associated with inflammatory diseases and their function is unclear. Here the authors show that PLD3/4 function as RNAses and deletion of these proteins in mice leads to accumulation of ssRNA which exacerbates inflammation through TLR signalling.
- Amanda L. Gavin
- , Deli Huang
- & David Nemazee
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Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS
Here, the authors perform transcriptional profiling on tracheal aspirates of adults requiring mechanical ventilation for SARS-CoV2-induced acute respiratory distress syndrome (ARDS) and identify a dysregulated host response predicted to predicted to be potentially modulated by dexamethasone.
- Aartik Sarma
- , Stephanie A. Christenson
- & Charles R. Langelier
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NK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence
During wound healing and infection in the skin there is a hypoxic environment involving HIF-1α and NK cells. Here the authors show that NK cells through HIF-1α provide a cross-regulatory balance to provide an adequate antimicrobial defence that can inhibit subsequent wound healing.
- Michal Sobecki
- , Ewelina Krzywinska
- & Christian Stockmann
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Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy
Iron is essential during pregnancy for embryo and placental development and maternal health. However, in this study using mouse models, the authors demonstrate that excess maternal iron causes adverse embryo outcomes in pregnancies with underlying systemic inflammation.
- Allison L. Fisher
- , Veena Sangkhae
- & Elizabeta Nemeth
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Genetic fate-mapping reveals surface accumulation but not deep organ invasion of pleural and peritoneal cavity macrophages following injury
Body cavity macrophages reside on the serous surfaces of organs and believed to participate in organ repair following injury. Here the authors show with a fate-mapping reporter system that these cells, although accumulate at the surfaces of injured liver or lung, don’t penetrate deeply into the tissue.
- Hengwei Jin
- , Kuo Liu
- & Bin Zhou
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Mitofusin-2 stabilizes adherens junctions and suppresses endothelial inflammation via modulation of β-catenin signaling
Endothelial tissues must have intact barrier function, but this may be disrupted during inflammation. Here, the authors show that the mitochondrial protein Mitofusin-2 stabilizes cell–cell adherens junctions in endothelial cells during homeostasis and binds the transcriptional activator β-catenin upon inflammatory stimulation.
- Young-Mee Kim
- , Sarah Krantz
- & Jalees Rehman
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Critical role of interferons in gastrointestinal injury repair
Despite being prevalent yet well studied, ulcerative colitis still has poorly characterized pathophysiology. Here the authors use mouse colitis models to find that type I and III interferon (IFN) both contribute to ameliorating the disease, with IFN signaling in either the epithelial or hematopoietic compartment sufficient for this protective effect.
- Constance McElrath
- , Vanessa Espinosa
- & Sergei V. Kotenko
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Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity
Mito-SEPs are small peptides that can modulate oxidative metabolism in mitochondria. Here the authors show that C15ORF48 encodes a mito-SEP, MOCCI, capable of altering mitochondria respiration to suppress inflammation, while C15ORF48 3’ untranslated region also contains a miRNA, miR-147b, that synergizes with MOCCI to modulate host anti-viral responses.
- Cheryl Q. E. Lee
- , Baptiste Kerouanton
- & Lena Ho
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Recruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells
The peritoneal cavity is a complicated myeloid niche containing a mixed population of resident macrophages and infiltrating cells that are responsive to inflammatory cues. Here the authors trace the fate of these infiltrating macrophages, their conversion to resident cells and how this is altered by the local inflammatory state over time.
- P. A. Louwe
- , L. Badiola Gomez
- & S. J. Jenkins
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Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages
IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.
- Jennifer K. Dowling
- , Remsha Afzal
- & Claire E. McCoy
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Conserved regulatory logic at accessible and inaccessible chromatin during the acute inflammatory response in mammals
Genetic elements that control inflammatory gene expression are not fully elucidated. Here the authors conduct a multi-species analysis of chromatin landscape and NF-κB binding in response to the proinflammatory cytokine TNFα, finding that conserved NF-κB bound regions are linked to enhancer activity and disease.
- Azad Alizada
- , Nadiya Khyzha
- & Michael D. Wilson
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| Open Access
Exposure to pesticides in utero impacts the fetal immune system and response to vaccination in infancy
Control of mosquito populations using pesticides is important for malaria elimination, but effects of pesticides on humans aren’t well understood. Here, Prahl et al. show in a cohort of pregnant Ugandan women and their infants that household spraying with bendiocarb affects the fetal immune system and response to vaccination in infancy.
- Mary Prahl
- , Pamela Odorizzi
- & Margaret E. Feeney
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Vascular surveillance by haptotactic blood platelets in inflammation and infection
Breakdown of vascular barriers is a major complication of inflammatory diseases. However, the mechanisms underlying platelet recruitment to inflammatory micro-environments remains unclear. Here, the authors identify haptotaxis as a key effector function of immune-responsive platelets
- Leo Nicolai
- , Karin Schiefelbein
- & Florian Gaertner
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Interleukin-1 receptor-induced PGE2 production controls acetylcholine-mediated cardiac dysfunction and mortality during scorpion envenomation
Cardiac dysfunction is a major complication that precedes death after scorpion envenomation. Here, authors show that heart failure and mortality are caused by excessive acetylcholine release, which requires IL-1R-dependent PGE2 production. Dexamethasone treatment effectively inhibits cardiac dysfunction and mortality.
- Mouzarllem B. Reis
- , Fernanda L. Rodrigues
- & Lúcia H. Faccioli
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Bacterial polyphosphates interfere with the innate host defense to infection
Production of polyphosphate polymers is a ubiquitous trait of bacteria. Here, the authors investigate the role of bacterial long polyphosphates in host immune suppression and show that long polyphosphates produced by E. coli inhibit LPS-mediated inflammation and bacterial clearance in mice.
- Julian Roewe
- , Georgios Stavrides
- & Markus Bosmann
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Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm
Tocilizumab has been used to treat the excessive inflammatory responses in COVID-19 patients. Here, the authors use single-cell RNA sequencing results from two severe COIVD-19 patients to provide high-dimensional immune profiling data, and to implicate potential cellular and molecular insights for the therapeutic effects of tocilizumab.
- Chuang Guo
- , Bin Li
- & Kun Qu
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| Open Access
STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression
TLR4 signalling can reprogram the metabolism of macrophages to be more glycolytic and proinflammatory. Here the authors show that LPS and TLR4 signalling results in recruitment of TBK1, which in turn phosphorylates serine 727 on STAT3 to enable a proinflammatory switch via an effect on mitochondrial metabolism.
- Jesse J. Balic
- , Hassan Albargy
- & Ashley Mansell
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| Open Access
Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma
Glucocorticoids (GC) are commonly used to suppress undesirable inflammatory responses. Here the authors show, using hi-dimensional flow cytometry data, that GC treatment following major surgeries alters adaptive immunity without significant modulation of innate immune responses or pain/functional impairment.
- Edward A. Ganio
- , Natalie Stanley
- & Brice Gaudilliere
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Article
| Open Access
Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling
Lactate is a by-product of glycolysis that can function via its G protein receptor GPR81. Here the authors show that LPS or Salmonella infection enhances glycolytic metabolism in bone marrow neutrophils, resulting in lactate production, which increases endothelial barrier permeability and mobilization of these neutrophils by targeting endothelial GPR81.
- Eman Khatib-Massalha
- , Suditi Bhattacharya
- & Tsvee Lapidot
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| Open Access
Immunological and inflammatory profiles in mild and severe cases of COVID-19
Immunophenotyping of patients with COVID-19 is ongoing, but much remains to be learned. Here the authors analyze 41 hospitalized patients with COVID-19 and show a higher degree of lymphopenia in various immune cell subsets as well as cytotoxicity and T cell inhibitory marker expression in severe cases compared with mild.
- Jin-Wen Song
- , Chao Zhang
- & Ji-Yuan Zhang
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Article
| Open Access
Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb
Reperfusion injury following myocardial ischemia is aggravated by inflammation and platelet–neutrophil complex formation. Here the authors show that semaphorin 7A binds to platelet GPIb, enhancing platelet–neutrophil interaction and increasing post-ischemic myocardial tissue injury, and that blockage of semaphorin 7A is protective.
- David Köhler
- , Tiago Granja
- & Peter Rosenberger
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Article
| Open Access
Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
Production of inflammatory mediators by M1-polarized macrophages is thought to rely on suppression of mitochondrial metabolism in favor of glycolysis. Refining this concept, here the authors define metabolic targets of nitric oxide as responsible for the mitochondrial rewiring resulting from polarization.
- Erika M. Palmieri
- , Marieli Gonzalez-Cotto
- & Daniel W. McVicar
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| Open Access
Brain-to-cervical lymph node signaling after stroke
Brain damage induces systemic inflammation, but insights and implication of this induction is still unclear. Here the authors show, using rat and mouse focal cerebral ischemia models, that the damaged brain signals via the VEGF-C/VEFGR3 axis to activate inflammatory responses in the draining cervical lymph nodes to induce systemic inflammation.
- Elga Esposito
- , Bum Ju Ahn
- & Kazuhide Hayakawa
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| Open Access
4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects
Redirection of the TCA cycle intermediate aconitate to itaconate production has anti-inflammatory effects. Here the authors show that the itaconate derivative 4-octyl-itaconate is anti-inflammatory partly as a result of inhibiting GAPDH enzymatic activity and thereby glycolysis in macrophages.
- Shan-Ting Liao
- , Chao Han
- & Ling-Yi Kong
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| Open Access
CD160 serves as a negative regulator of NKT cells in acute hepatic injury
BTLA is established as a negative regulator of natural killer T (NKT) cell function, and share its ligand HVEM with CD160. Here the authors show, by analyzing NKT activation in CD160-deficient mice or with BTLA blockade, that CD160 synergizes with BTLA to negatively regulate NKT cells during hepatic injury.
- Tae-Jin Kim
- , Gayoung Park
- & Kyung-Mi Lee
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| Open Access
Inflammation triggers immediate rather than progressive changes in monocyte differentiation in the small intestine
Bone marrow-derived monocytes are recruited to the gut to replenish the local macrophage pool. Here the authors show that, while such replenishment constitutively occur under homeostasis, gut inflammation induces an immediate, Trem1-related transcription change to recruited monocyte to enable a context-dependent modulation of macrophage functions.
- Girmay Desalegn
- & Oliver Pabst
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| Open Access
Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation
EZH2-mediated methylatation of histone 3 is essential for immune regulation. Here, the authors show that EZH2 inhibitors attenuate experimental colitis in mice by promoting the development of myeloid-derived suppressor cells, and delay the onset of colitis-associated cancer.
- Jie Zhou
- , Shuo Huang
- & Bo Zhu
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| Open Access
Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis
The capsular polysaccharide A (PSA) of Bacteroides fragilis is known to have immunomodulatory capability during sterile inflammatory disorders. Here Ramakrishna and colleagues show that PSA administration in a murine model of herpes simplex encephalitis induces IL-10 producing B and T cell populations that confer protection against lethal challenge and brain pathology.
- Chandran Ramakrishna
- , Maciej Kujawski
- & Edouard M. Cantin
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| Open Access
Lipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace
The diversity of human mononuclear phagocyte subsets remains to be characterized in many tissue-specific and functional contexts, including pulmonary inflammation. Here the authors characterize dendritic cell and monocyte subset recruitment to the bronchoalveolar space in a human LPS inhalation model.
- Laura Jardine
- , Sarah Wiscombe
- & A. John Simpson
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| Open Access
Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair
Neutrophils and macrophages are both involved in the initiation of inflammation, but whether and how they may participate in inflammation resolution is unclear. Here the authors show that neutrophils may mediate the conversion of macrophage into a pro-resolution phenotype via reactive oxygen species production to promote liver repair.
- Wenting Yang
- , Yuandong Tao
- & Li Tang
PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury