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| Open AccessExosomal secreted SCIMP regulates communication between macrophages and neutrophils in pneumonia
In this work, authors report on SCIMP-positive exosomes secreted by macrophages, that play a crucial anti-inflammatory role in pneumonia. Exosomal SCIMP primarily achieves bacterial clearance by the SCIMP-FPRs-neutrophils chemotaxis.
- Xiaolei Pei
- , Li Liu
- & Sizhou Feng
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Article
| Open AccessT cell migration requires ion and water influx to regulate actin polymerization
The ability of T cells to migrate is a central component of their functionality and is known to require WNK1 kinase that is linked to the influx of ions into the cell. Here the authors show that T cell migration requires WNK1 mediated ion and water influx to swell the membrane of the leading edge and support actin polymerisation and forward motility.
- Leonard L. de Boer
- , Lesley Vanes
- & Victor L. J. Tybulewicz
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| Open AccessDietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15
Environmental factors such as diet have been shown to be involved with the development of colitis. Here the authors show that L-tryptophan promotes the development of GPR15+ Treg cells via the host IDO1/2 pathway and that tryptophan consumption in mice reduces severity of colitis in a C. rodentium mouse model.
- Nguyen T. Van
- , Karen Zhang
- & Sangwon V. Kim
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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 AccessPeripheral 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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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 AccessStructural basis of dimerization of chemokine receptors CCR5 and CXCR4
Here, authors report chemokine receptors structures obtained using coarse-grained metadynamics. CCR5 and CXCR4 homo- and heterodimers differ in the conformations of ligand binding sites and of the G protein interaction interface, suggesting structural basis for the rational design of biased ligands.
- Daniele Di Marino
- , Paolo Conflitti
- & Vittorio Limongelli
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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 AccessDiscovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling
Ticks inject evasins at the bite site to bind multiple redundant chemokines and inhibit inflammation allowing blood feeding. Here, the authors identify evasin derived short peptides with broad spectrum anti-chemokine activity that could be used to develop new treatments for inflammatory disease.
- Serena Vales
- , Jhanna Kryukova
- & Shoumo Bhattacharya
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Article
| Open AccessLILRB2/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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Article
| Open AccessEngineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
Tick evasin proteins block the inflammatory activity of mammalian chemokines. In this work, the authors report that structure-based modification of class A3 evasins alters their chemokine selectivity, suggesting these evasins could be engineered for targeted anti-inflammatory therapy.
- Shankar Raj Devkota
- , Pramod Aryal
- & Martin J. Stone
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Article
| Open AccessStructural basis of CXC chemokine receptor 1 ligand binding and activation
Chemokines are small proteins secreted at sites of injury. Here, the authors describe the structure of the chemokine receptor CXCR1 bound to chemokine CXCL8, solved by cryo-EM. The model helps explain the ligand preferences of this receptor.
- Naito Ishimoto
- , Jae-Hyun Park
- & Sam-Yong Park
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Article
| Open AccessPersistent 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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Article
| Open AccessPriming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors
It has been reported that inhibition of the epigenetic regulator DNA methyltransferase 1 (DNMT1) is associated with improved response to immune checkpoint blockade (ICB). Here the authors show that conditional deletion of Dnmt1 in endothelial cells is sufficient to promote T cell infiltration, reduce tumor growth and enhance ICB response in preclinical models.
- Dae Joong Kim
- , Swetha Anandh
- & Andrew C. Dudley
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Article
| Open AccessInhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment
m6A modification has been reported to play roles in many developmental and pathological processes, but its role in AKI remains poorly understood. Here, the authors show the role and the mechanism of the m6A demethylase, ALKBH5 on IRI induced AKI.
- Juntao Chen
- , Cuidi Xu
- & Tongyu Zhu
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Article
| Open AccessTargeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction
Therapeutic interference with the immune response after myocardial infarction holds the potential to close a clinically relevant gap. Here, the authors show that inhibition of a cardiomyocyte-specific ADAM10 / CX3CL1 axis improves post infarction survival and cardiac function by attenuating neutrophil-mediated myocardial damage.
- Erik Klapproth
- , Anke Witt
- & Ali El-Armouche
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Article
| Open AccessMaturation and specialization of group 2 innate lymphoid cells through the lung-gut axis
The developmental process of group 2 innate lymphoid cells (ILC2) involves migration between different internal organs. Here the authors show that ILC2s migrate from the lung to the intestine to undergo maturation after treatment with IL-33 and that lung and intestine ILC2s have a different phenotype.
- Min Zhao
- , Fei Shao
- & Shuo Wang
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Article
| Open AccessCXCL13 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 AccessLocation bias contributes to functionally selective responses of biased CXCR3 agonists
Subcellular signaling is critical to generating cellular responses that modulate inflammatory pathways at the chemokine receptor CXCR3. Eiger et al. determine that agonist-biased CXCR3 signaling at endosomes differs from that at the plasma membrane, proposing location bias as an important phenomenon in signal transduction.
- Dylan Scott Eiger
- , Noelia Boldizsar
- & Sudarshan Rajagopal
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Article
| Open AccessSingle-atom nanozymes catalytically surpassing naturally occurring enzymes as sustained stitching for brain trauma
The catalytic activity of regenerable nanozymes is currently the bottle neck for their wider employment. Here, the authors report on single-atom nanozymes of RhN4, VN4, and Fe-Cu-N6 with higher catalytic activities than natural enzymes, and demonstrate the Rh/VN4 recyclability and scalp healing properties in bioactive sutures.
- Shaofang Zhang
- , Yonghui Li
- & Xiao-Dong Zhang
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Article
| Open AccessCXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes
The chemokine, CXCL4, is proposed to enhance Toll-like receptor (TLR) signaling by facilitating TLR ligand import. Here the authors show that CXCL4 also synergizes with TLR8 to promote the activation of TBK1 and IKKε and induce epigenetic remodeling of relevance inflammatory genes to enhance inflammatory responses in human monocytes.
- Chao Yang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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Article
| Open AccessViral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 cell pulmonary influx
Viral coinfection alongside mycobacterium tuberculosis (Mtb) infection may lead to immune complications or interference with immune responses. Here the authors show that in mice infected with Mtb and LCMV virus the specific TH1 response to MTb is reduced through a type I IFN response to the infecting virus.
- Tae Gun Kang
- , Kee Woong Kwon
- & Sung Jae Shin
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Article
| Open AccessLow CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry
Here, Claireaux et al. show that people who naturally control HIV infection express lower levels of the viral co-receptor CCR5 in specific CD4+ T cells, and that this results from mutations or receptor internalization by CD4+ T cell-produced chemokines.
- Mathieu Claireaux
- , Rémy Robinot
- & Lisa A. Chakrabarti
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Article
| Open AccessGPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models
Immunologically cold tumours don’t respond to immune checkpoint blockade inhibition due to poor recruitment of anti-tumour T cells. Authors show here that melanoma-associated lymphatic endothelial cells express G Protein-Coupled Receptor 182 that scavenges CXCL9 and other chemokines necessary for T cell recruitment.
- Robert J. Torphy
- , Yi Sun
- & Yuwen Zhu
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Article
| Open AccessProteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction
Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.
- Caroline Diorio
- , Rawan Shraim
- & Edward M. Behrens
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Article
| Open AccessBrown adipose tissue monocytes support tissue expansion
Adipose tissue is composed of a number of adipocytes and a number of other cells including immune cells. Here the authors use single-cell sequencing of murine brown adipose tissue immune cells and describe multiple macrophage and monocyte subsets and show that monocytes contribute to brown adipose tissue expansion.
- Alexandre Gallerand
- , Marion I. Stunault
- & Stoyan Ivanov
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Article
| Open AccessMalaria parasites both repress host CXCL10 and use it as a cue for growth acceleration
The chemokine CXCL10 is associated with pathogenesis of cerebral malaria in Plasmodium falciparum infection. Here the authors show that P. falciparum produces extracellular vesicles laden with RNAs that are taken up by monocytes resulting in a RIG-I and HUR-1 mediated mechanism of inhibition of CXCL10 protein translation.
- Yifat Ofir-Birin
- , Hila Ben Ami Pilo
- & Neta Regev-Rudzki
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Article
| Open AccessCD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells
The cellular and molecular mechanisms underlying the resolution of non-alcoholic steatohepatitis remain incompletely understood. Here the authors report a single cell-based analysis that identified CD8 + tissue-resident memory T cells, which contribute to resolution of liver fibrosis potentially via elimination of hepatic stellate cells through Fas-mediated cytotoxicity.
- Yuzo Koda
- , Toshiaki Teratani
- & Nobuhiro Nakamoto
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Article
| Open AccessA sand fly salivary protein acts as a neutrophil chemoattractant
Immune mimicry has been shown in chemokine like moieties from bacteria and viruses. Here, the authors characterise a sand fly salivary protein that induces neutrophil chemotaxis and explore its impact in a model of parasitic infection.
- Anderson B. Guimaraes-Costa
- , John P. Shannon
- & Fabiano Oliveira
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Article
| Open AccessCCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer
Only a limited proportion of patients with non-small cell lung cancer respond to anti-PD-1/PD-L1 immunotherapy. Here, the authors show that in autochthonous models of KRAS-mutated lung cancer, CCL7 promotes cDC1 infiltration into the lungs, sustaining antitumor immune responses and potentiating anti-PD1 treatment efficacy.
- Man Zhang
- , Wei Yang
- & Bo Zhong
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Article
| Open AccessAndrogen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion
Anti-androgen therapy inhibits prostate cancer (PC) progression, and is thought to act directly on cancer cells. Here the authors show that androgen receptor is expressed on normal and PC-associated macrophages, and its stimulation alters macrophage secretome to promote migration of cultured PC cell lines.
- Bianca Cioni
- , Anniek Zaalberg
- & Andries M. Bergman
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Article
| Open AccessInhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury
Chronic inflammation is a feature of age-related regenerative decline in skeletal muscles, but how it directly affects resident muscle stem cell fate and function is unclear. Here, the authors show that Ccr2 signaling in muscle stem cell derived progenitors represses terminal myogenic differentiation, and that targeting Ccr2 on aged myogenic progenitors rejuvenates aged skeletal muscle healing and function.
- Roméo S. Blanc
- , Jacob G. Kallenbach
- & Joe V. Chakkalakal
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Article
| Open AccessSLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling
Macrophages survey their surroundings using macropinocytosis, but its regulation is unclear. Here, the authors report that SLIT2, a known inhibitor of Rac GTPases, is an endogenous inhibitor of macropinocytosis, and that SLIT2 limits the uptake of NOD2 ligands into immune cells and subsequent release of the inflammatory chemokine, CXCL1, in vivo.
- Vikrant K. Bhosle
- , Tapas Mukherjee
- & Lisa A. Robinson
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Article
| Open AccessB cell zone reticular cell microenvironments shape CXCL13 gradient formation
Morphogens such as chemokines form gradients to direct graded responses and modulate cell behaviors. Here the authors show, using imaging and computer simulation, that the chemokine CXCL13 originated from follicular reticular cells in the lymph nodes forms both soluble and immobilized gradients to regulate B cell recruitment and migration.
- Jason Cosgrove
- , Mario Novkovic
- & Mark C. Coles
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Article
| Open AccessAndrogens predispose males to monocyte-mediated immunopathology by inducing the expression of leukocyte recruitment factor CXCL1
Altered monocyte responses and testosterone levels correlate, individually, with the pathogenesis of hepatic amebiasis in mice. Here the authors show that testosterone induces enhanced TNF/CXCL1 expression and stronger proinflammatory responses in both human and mouse monocytes to support an androgen-monocyte axis of inflammation regulation.
- Julie Sellau
- , Marie Groneberg
- & Hannelore Lotter
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Article
| Open AccessThe atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides
Opioids modulate pain, anxiety and stress by activating four subtypes of opioid receptors. The authors show that atypical chemokine receptor 3 (ACKR3) is a scavenger for various endogenous opioid peptides regulating their availability without activating downstream signaling.
- Max Meyrath
- , Martyna Szpakowska
- & Andy Chevigné
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Article
| Open AccessRunx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity
CCL5 is an important chemokine for modulation of inflammatory responses, but how CCL5 expression is regulated is still unclear. Here the authors show that the CCL5 locus contains two enhancers, with the proximal enhancer being responsible for homeostatic expression and the distal enhancer enforcing inducibility, while both enhancers are modulated by RUNX3.
- Wooseok Seo
- , Kanako Shimizu
- & Ichiro Taniuchi
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Article
| Open AccessEfficient homing of T cells via afferent lymphatics requires mechanical arrest and integrin-supported chemokine guidance
Immune cells mostly enter lymph nodes (LN) from blood circulation, but whether afferent lymphatics contributes to LN entry is unclear. Here, the authors show, using a photo-convertible reporter, that T cells in afferent lymphatics frequently enter LN and become arrested in the subcapsular sinus, with chemokines and integrins further guiding their migration in the LN.
- Rieke Martens
- , Marc Permanyer
- & Reinhold Förster
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Article
| Open AccessCXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis
CXCL4 is an inflammatory chemokine signaling through CXCR3 receptor. Here the authors show a CXCR3-independent function of CXCL4: it forms liquid crystals with DNA, potentiating mammalian and bacterial DNA recognition by TLR9, thereby amplifying interferon-a production in systemic sclerosis.
- Roberto Lande
- , Ernest Y. Lee
- & Loredana Frasca
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Article
| Open AccessHuman Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments
At inflammatory sites, ectopic lymphoid-like structures (ELS) can be induced through the function of chemokine CXCL13 produced by CD4+ T cells. Here the authors show that a transcription factor, Sox4, induces the expression of CXCL13 in CD4 T cells in vitro, and is associated with ELS formation in patients with rheumatoid arthritis.
- Hiroyuki Yoshitomi
- , Shio Kobayashi
- & Junya Toguchida
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Article
| Open AccessChemokines cooperate with TNF to provide protective anti-viral immunity and to enhance inflammation
Cytokines play critical roles in the anti-viral response but their contribution in vivo remains unclear. Here the authors show that viral CrmD is a major virulence determinant and requires the SECRET and TNF binding domains to counter both the chemokine and cytokine driven inflammatory defenses.
- Alí Alejo
- , M. Begoña Ruiz-Argüello
- & Antonio Alcamí
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Article
| Open AccessObesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment
Inflammation can be induced by obesity, and has been linked with onset of colorectal cancer (CAC). Here the authors show in mouse models that obesity-induced interleukin-6 alters macrophage function to enhance CCL-20/CCR-6-mediated recruitment of B cells and γδ T cells, thereby promoting gut inflammation and CAC progression.
- Claudia M. Wunderlich
- , P. Justus Ackermann
- & F. Thomas Wunderlich
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Article
| Open AccessACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity
The atypical chemokine receptor ACKR2 regulates immune responses. Here the authors confirm that ACKR2 depletion promotes primary tumor growth but show it has an anti-metastatic effect in mouse models of breast cancer by affecting myeloid differentiation and unleashing the anti-metastatic activity of neutrophils.
- Matteo Massara
- , Ornella Bonavita
- & Raffaella Bonecchi
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Article
| Open AccessMicrobial volatile communication in human organotypic lung models
There is a need for improved in vitro models of host-microbe interactions in the lung. Here, Barkal et al. present a microscale organotypic model of the human bronchiole for studying pulmonary infection, including volatile compound communication between microbial populations and host cells.
- Layla J. Barkal
- , Clare L. Procknow
- & David J. Beebe
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Article
| Open AccessROCK regulates the intermittent mode of interstitial T cell migration in inflamed lungs
ROCK is associated with T cell movement in lymph nodes. Here the authors use an LPS lung damage model and two-photon imaging to show that CD8+ T cells in lung tissue engage in ROCK-dependent fast linear migration alternating with bursts of slower confined migration that together optimize contact with target cells.
- Paulus Mrass
- , Sreenivasa Rao Oruganti
- & Judy L. Cannon
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Article
| Open AccessIL-17-producing γδ T cells switch migratory patterns between resting and activated states
IL-17-producing γδ T (γδT17) cells position in barrier tissues but also home to inflammatory sites. How this trafficking is regulated is unclear. Here the authors show that the dynamic expression of chemokine receptors CCR2 and CCR6 differentiates γδT17 cell trafficking patterns at homeostasis and in inflammatory scenarios.
- Duncan R. McKenzie
- , Ervin E. Kara
- & Shaun R. McColl
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Article
| Open AccessMonocyte-derived inflammatory Langerhans cells and dermal dendritic cells mediate psoriasis-like inflammation
Imiquimod exacerbates IL-23-induced skin inflammation and models psoriasis in mice. Here the authors show that this pathology is not dependent on resident dendritic cells, but on CCR6-induced immigration of monocyte-derived cells.
- Tej Pratap Singh
- , Howard H. Zhang
- & Joshua M. Farber
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Article
| Open AccessLTβR controls thymic portal endothelial cells for haematopoietic progenitor cell homing and T-cell regeneration
Lymphoid progenitors migrate from the bone marrow into the thymus to give rise to T and NK cell lineages. Here the authors characterize a lymphotoxin receptor beta-dependent population of thymic endothelial cells that guide lymphoid progenitor homing in the thymus.
- Yaoyao Shi
- , Weiwei Wu
- & Mingzhao Zhu
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Article
| Open AccessZero-temperature quantum annealing bottlenecks in the spin-glass phase
Quantum annealing can solve hard optimization problems, but it is limited by computational bottlenecks. Here, the author obtains the scaling of spin-glass bottlenecks with the problem size and explains a crossover to exponential complexity for large sizes.
- Sergey Knysh