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Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis
The TAM tyrosine kinases, Axl and MerTK, have been implicated in rheumatoid arthritis (RA). Here, using a synovial tissue bioresource of patients with RA, the authors describe how Axl and MerTK expression and function are linked to synovial histopathology, disease activity, and therapeutic intervention with IL-6 inhibitors.
- Alessandra Nerviani
- , Marie-Astrid Boutet
- & Costantino Pitzalis
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Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
P2Y14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y14R as a promising target for treatment of UC.
- Chunxiao Liu
- , Hui Wang
- & Qinghua Hu
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Evidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis
Podoconiosis is triggered by long term barefoot exposure to volcanic red clay soil. Here, Negash et al characterise the immune profile of podoconiosis patients to show this disease is associated with high levels of immune activation and inflammation.
- Mikias Negash
- , Menberework Chanyalew
- & Melanie J. Newport
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A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Unlike most inflammatory fibrotic conditions, frozen shoulder is a spontaneously self-resolving human disease. Here authors study samples from frozen shoulder capsules by single cell RNA sequencing and by microculture modelling of cell-cell interactions to conclude that specific macrophage populations and their interaction with fibroblasts might promote fibrosis resolution.
- Michael T. H. Ng
- , Rowie Borst
- & Stephanie G. Dakin
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Single-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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Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease
Cigarette smoking is an established risk factor for inflammatory bowel disease. The authors suggest that smoking may affect the risk of Crohn’s disease and ulcerative colitis by modulating the DNA methylation status of the DNMT3A, LTA/TNF, and AHRR region, respectively.
- Han Zhang
- , Rahul Kalla
- & Xue Li
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IKKε and TBK1 prevent RIPK1 dependent and independent inflammation
TBK1 and IKKε are involved in the regulation of a range of cellular and inflammatory processes. Here Eren and colleagues discern a role for IKKε in preventing RIPK1-dependent and RIPK1-independent inflammation in mice lacking TBK1 kinase activity.
- Remzi Onur Eren
- , Göksu Gökberk Kaya
- & Manolis Pasparakis
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Article
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Serglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration
Aging-related intervertebral disc degeneration (IVDD) is a leading cause of lower back pain. Here, the authors perform scRNA-seq analysis of intervertebral disc cells from patients, and identify cell populations and mechanisms associated with IVDD.
- Fan Chen
- , Linchuan Lei
- & Jianru Wang
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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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TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.
- Gang Liu
- , Tatt Jhong Haw
- & Philip M. Hansbro
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Article
| Open Access
Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.
- Yuichi Tsuchiya
- , Takao Seki
- & Hiroyasu Nakano
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Article
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CREB1-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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A CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans
Extra-intestinal “creeping fat” is a hallmark of Crohn’s disease. Here, using single-cell transcriptomics and lipid metabolomics, the authors identify a subset of mesenchymal stem cells that promote adipogenesis in creeping fat formation.
- Fengfei Wu
- , Fangting Wu
- & Lan Bai
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γδ T cells control murine skin inflammation and subcutaneous adipose wasting during chronic Trypanosoma brucei infection
Trypansome brucei infection can result in colonisation of the skin but how this impacts the skin architecture and immune response has not been fully resolved. Here the authors apply a spatially resolved single cell transcriptomics approach in a murine model of infection, and suggest a role for IL-17- producing γδ T cells in the immune response to T. brucei skin infection.
- Juan F. Quintana
- , Matthew C. Sinton
- & Annette MacLeod
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A single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia
Achalasia is a rare motility disorder of the esophagus resulting from abnormal immune responses, but the immunologic mechanism is unclear. Here the authors use scRNA-seq of PBMC and esophageal lower sphincter tissue and find C1QC+ macrophages and tissue-resident memory T cells with expanded compositions and altered transcriptional profiles in achalasia.
- Zu-Qiang Liu
- , Hao Dai
- & Quan-Lin Li
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Effect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes
A beneficial effect of parasitic worms on metabolic health has been postulated based on epidemiological and animal studies. Here, the authors show in a phase I clinical trial that treatment of people at risk of type 2 diabetes with hookworms is safe and may improve key measures of metabolic health.
- Doris R. Pierce
- , Malcolm McDonald
- & Paul R. Giacomin
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LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis
Inhibition of immunocyte infiltration and activation has been suggested to ameliorate hepatic inflammation and fibrosis in nonalcoholic steatohepatitis. Here, the authors show PirB/LILRB2 regulates the migration of macrophages during NASH by binding with ANGPTL8, which is involved in the regulation of NASH development.
- Dan-Pei Li
- , Li Huang
- & Xue-Feng Yu
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Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID
Post-acute sequelae of COVID-19 (PASC) has heterogenous presentation and complex etiology. Here the authors profile peripheral blood of patients with PASC and analyze by machine-learning to identify immune and serology features that allow the stratification of PASC into inflammatory and non-inflammatory types for better diagnosis and therapy-planning.
- Matthew C. Woodruff
- , Kevin S. Bonham
- & Ignacio Sanz
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Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
Rosacea is a common, multi-factorial chronic inflammatory skin disorder. Here authors provide evidence of genetic predisposition by whole genome sequencing and whole exome sequencing of samples from familial cases, and by recapitulating a recurrent mutation in the LRRC4 gene in a mouse model, they find that neuron-derived vasoactive intestinal peptide is an important pathogenic factor for neurogenic inflammation in rosacea.’
- Zhili Deng
- , Mengting Chen
- & Ji Li
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Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis
Changes in Psoriasis and other inflammatory skin diseases during severity stages can be investigated using single cell and spatial transcriptomics. Here the authors compare different inflammatory skin diseases to emphasise differences in immune cells and inflammatory markers particularly keratinocytes and fibroblasts.
- Feiyang Ma
- , Olesya Plazyo
- & Johann E. Gudjonsson
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Persistent serum protein signatures define an inflammatory subcategory of long COVID
Long COVID or post-acute sequelae of SARS-CoV-2 is defined by persisting chronic symptoms following acute SARS-CoV-2 infection but represent an aetiologically diverse group of disorders. Here authors identify molecularly distinct subtypes, including a form with persistent inflammation, via longitudinal analysis of serum proteome.
- Aarthi Talla
- , Suhas V. Vasaikar
- & Troy R. Torgerson
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Intrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease
Chronic kidney disease (CKD) is a disease that irreversibly leads to loss of renal function. Here, the authors demonstrate the beneficial effect of intrinsic TGF-b signaling on mitochondrial function and inflammation in the proximal tubule epithelium in response to kidney injury.
- Merve Kayhan
- , Judith Vouillamoz
- & Stellor Nlandu Khodo
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AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling
Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.
- Xingwen Da
- , Ziyan Li
- & Qing K. Wang
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Article
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Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Mast cells are activated and proliferate during allergic reactions which can involve mast cell specific proteins. Here the authors show that mast cell-expressed membrane protein1 (MCEMP1) is an adaptor for KIT to promote SCF mediated mast cell proliferation and lack of MCEMP1 reduces inflammation in mouse asthma models.
- Youn Jung Choi
- , Ji-Seung Yoo
- & Jae U. Jung
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Article
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Tenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis
Local cues for hyperinnervation in chronic skin diseases are not fully understood. Here, the authors show that a distinct subset of dermal papillary fibroblasts promote neurite outgrowth and facilitate neuron-immune interactions through extracellular matrix remodeling in a mouse model of psoriasis
- Xiaojie Cai
- , Maoying Han
- & Honglin Wang
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Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.
- Adriana A. de Jesus
- , Guibin Chen
- & Raphaela Goldbach-Mansky
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mTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome
Still’s disease is an inflammatory syndrome linked to the development of further immune dysregulation and hypercytokinaemia termed macrophage activation syndrome. Here the authors implicate the mechanistic target of rapamycin complex 1 in murine models of Still’s disease and macrophage activation syndrome, and provide associations with clinical cases in patients
- Zhengping Huang
- , Xiaomeng You
- & Pui Y. Lee
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GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages
G-protein-signaling modulator 1 (GPSM1), an accessory protein which activates heterotrimeric G-protein signaling, exhibits a genetic association with type 2 diabetes. Here the authors show that myeloid GPSM1 ablation in mice inhibits inflammation and metabolic dysfunction upon high fat diet.
- Jing Yan
- , Yuemei Zhang
- & Cheng Hu
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JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development remains unknown. Here, the authors show that JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
- Rida Al-Rifai
- , Marie Vandestienne
- & Hafid Ait-Oufella
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Article
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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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| Open Access
Divergent regulation of basement membrane trafficking by human macrophages and cancer cells
Cancer cells and macrophages can infiltrate and remodel the extracellular matrix (ECM). Here, by using native basement membrane-interstitial matrix explants as model and live cell confocal imaging, the authors reveal divergent mechanisms used by cancer cells and macrophages to penetrate native basement membrane barriers.
- Julian C. Bahr
- , Xiao-Yan Li
- & Stephen J. Weiss
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Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Identifying the mechanisms underlying the early inflammatory phase of aortic valve disease is crucial for disease prevention. Here the authors perform single-cell RNA sequencing to show the immunomodulatory role of PPARγ in valvular endothelial cells during hyperlipidemia.
- Seung Hyun Lee
- , Nayoung Kim
- & Jae-Hoon Choi
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Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2
Adipocyte tissue macrophages (ATM) are recruited and activated in obesity. The authors show that adipocytes release lactate as a signal of inflammation and that this metabolite can enhance obesity associated inflammation through stimulation of ATM by direct binding with PHD2.
- Tianshi Feng
- , Xuemei Zhao
- & Xiaoyan Hui
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Context-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march
Allergic sensitisation in the skin can lead to allergic dermatitis and further to airway asthma in a process of atopic march. Here the authors examine the difference between superficial or deep skin sensitisation, characterise the immune cells generated and show differential TSLP and IL-1β involvement.
- Justine Segaud
- , Wenjin Yao
- & Mei Li
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In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response
The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.
- Juliane Glaubitz
- , Anika Wilden
- & Matthias Sendler
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Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice
Adipose immune cells contribute to obesity-related disease, but less is known about weight cycling. Here, authors show that weight loss reduces diabetes risk, but inflammatory adipose immune cell populations persist and may contribute to worsened diabetes risk upon weight regain.
- Matthew A. Cottam
- , Heather L. Caslin
- & Alyssa H. Hasty
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Article
| Open Access
IL-1R-IRAKM-Slc25a1 signaling axis reprograms lipogenesis in adipocytes to promote diet-induced obesity in mice
TLRs/IL-1R signaling play a role in high-fat diet induced adipose tissue dysfunction and obesity-associated metabolic syndrome. Here the authors report that adipocyte-specific deficiency of IL-1 Receptor-Associated Kinase M (IRAKM) ameliorates diet induced obesity, potentially via the mitochondrial citrate carrier Slc25a1 and reduced de novo lipogenesis.
- Weiwei Liu
- , Hao Zhou
- & Xiaoxia Li
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Article
| Open Access
Genetic analysis of over half a million people characterises C-reactive protein loci
Inflammation is associated with a variety of diseases. Here, the authors identify 266 genetic loci associated with C-reactive protein levels, a marker of inflammation, in >500,000 Europeans, along with associated pathways, clinical outcomes and potential causal associations with disease.
- Saredo Said
- , Raha Pazoki
- & Abbas Dehghan
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Article
| Open Access
Loss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures
Loss of canonical Notch signaling in vascular endothelial cells induces spontaneous formation of proto-typical tertiary lymphoid structures in mouse kidney, liver and lungs, which form around central arteries that acquire a high endothelial cell signature
- Susanne Fleig
- , Tamar Kapanadze
- & Florian P. Limbourg
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| Open Access
TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease
Reduction of systemic autoimmunity using TNF blockers may also reduce inflammatory diseases in other organs. Here, the authors use a patient database and scRNA-seq to link autoimmune diseases to benign prostatic hyperplasia (BPH), and demonstrate that prostatic hyperplasia is reduced by TNF blockers in humans and mice.
- Renee E. Vickman
- , LaTayia Aaron-Brooks
- & Simon W. Hayward
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Article
| Open Access
Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation
Pannexin-1 ion channels on endothelial cells regulate vascular inflammation and remodeling to mediate aortic aneurysm formation. Pharmacological blockade of Pannexin-1 channels may offer translational therapeutic mitigation of aneurysmal pathology.
- Amanda C. Filiberto
- , Michael D. Spinosa
- & Ashish K. Sharma
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| Open Access
TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy
The immunopathology of Duchenne Muscular Dystrophy includes a disturbed balance of pro and anti-inflammatory macrophages. Here the authors implicate trained innate immunity in a murine model of the disease, and reveal TLR4 as a key regulator of this process.
- Salyan Bhattarai
- , Qian Li
- & Basil J. Petrof
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| Open Access
TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models
Expansion of synovial fibroblast is associated with rheumatoid arthritis (RA) progression, but how this expansion is regulated is still not clear. Here the authors use a mouse RA model, single cell RNA sequencing and in vitro analyses to show that inducing ferroptosis and suppressing TNF signaling reduce fibroblast numbers and ameliorate experimental arthritis.
- Jiao Wu
- , Zhuan Feng
- & Ping Zhu
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Article
| Open Access
C-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis
The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis.
- Inhye Park
- , Michael E. Goddard
- & Claudia Monaco
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MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
MDA5 is the primary immune sensor for SARS-CoV-2 and many other viruses. Mutations in MDA5 can cause disease. Here the authors employ CryoEM and biochemical methods to show how steric constraints cause MDA5 to misrecognize endogenous RNA as viral RNA.
- Qin Yu
- , Alba Herrero del Valle
- & Yorgo Modis
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| Open Access
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice
OTULIN is a negative regulator of linear ubiquitination, and its deficiency in human causes multi-organ inflammations including the skin. Here the authors show, by combining various genetic tools with epidermis-specific Otulin knockout mice, that Otulin suppresses skin inflammation predominantly by inhibiting RIPK1-mediated keratinocytes necroptosis.
- Hannah Schünke
- , Ulrike Göbel
- & Manolis Pasparakis
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Article
| Open Access
CD127+ CD94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with Crohn’s disease
Phenotypic markers that overlap between ILC1 and NK populations have impacted the robust and specific analysis of these immune cell populations. Employing scRNA sequencing here the authors identify CD127+ CD94+ innate lymphoid cells that express granulysin and perforin and are expanded in patients with Crohn’s disease.
- L. Krabbendam
- , B. A. Heesters
- & H. Spits
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| Open Access
Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice
Asthma is caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation.
- Eva Conde
- , Romain Bertrand
- & Laurent L. Reber
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Article
| Open Access
Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis
Dysregulation of synovial fibroblasts is thought to be an important step in the pathogenesis of rheumatoid arthritis. Here the authors implicate α2-6 sialylation in this process by studying the glycome of these cells in patients and in a mouse model of inflammatory joint disease.
- Yilin Wang
- , Aneesah Khan
- & Miguel A. Pineda
IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model