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1.
Front Immunol ; 13: 966591, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059556

RESUMO

Leukocyte chemotactic factor 2-associated (ALECT2) amyloidosis is one of the recently reported types of amyloidosis, which is caused by the extracellular deposition of leukocyte chemotactic factor 2 (LECT2). There have not been any reports involving the concurrence of ALECT2 amyloidosis with Sjögren's syndrome (SS) or systemic lupus erythematosus (SLE)s. Herein, we report a case of a 68-year-old Chinese woman presenting with long duration of sicca symptoms. The clinical evaluation and laboratory findings showed that she had SS overlapped with SLE. Kidney biopsy revealed a membranoproliferative glomerulonephritis (MPGN) with glomerular deposition of dominant IgG3-kappa by immunofluorescene, which was related to SS/SLE. Furthermore, patchy congophilic amyloid deposits in the tubulointerstitium were detected, which were positive for LECT2 protein by immunohistochemical staining and immunoelectron microscopy. This is the first case of ALECT2 amyloidosis that coexisted with SS/SLE, and the causal relationship between ALECT2 amyloidosis and autoimmune diseases remain unclear.


Assuntos
Amiloidose , Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Idoso , Amiloidose/diagnóstico , Amiloidose/etiologia , Amiloidose/metabolismo , Doenças Autoimunes/diagnóstico , Fatores Quimiotáticos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Leucócitos/metabolismo
2.
Nat Commun ; 13(1): 5232, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064945

RESUMO

The formyl peptide receptor 1 (FPR1) is primarily responsible for detection of short peptides bearing N-formylated methionine (fMet) that are characteristic of protein synthesis in bacteria and mitochondria. As a result, FPR1 is critical to phagocyte migration and activation in bacterial infection, tissue injury and inflammation. How FPR1 distinguishes between formyl peptides and non-formyl peptides remains elusive. Here we report cryo-EM structures of human FPR1-Gi protein complex bound to S. aureus-derived peptide fMet-Ile-Phe-Leu (fMIFL) and E. coli-derived peptide fMet-Leu-Phe (fMLF). Both structures of FPR1 adopt an active conformation and exhibit a binding pocket containing the R2015.38XXXR2055.42 (RGIIR) motif for formyl group interaction and receptor activation. This motif works together with D1063.33 for hydrogen bond formation with the N-formyl group and with fMet, a model supported by MD simulation and functional assays of mutant receptors with key residues for recognition substituted by alanine. The cryo-EM model of agonist-bound FPR1 provides a structural basis for recognition of bacteria-derived chemotactic peptides with potential applications in developing FPR1-targeting agents.


Assuntos
Padrões Moleculares Associados a Patógenos , Staphylococcus aureus , Fatores Quimiotáticos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , N-Formilmetionina Leucil-Fenilalanina/química , Neutrófilos/metabolismo , Padrões Moleculares Associados a Patógenos/metabolismo , Peptídeos/metabolismo , Staphylococcus aureus/metabolismo
3.
Biophys J ; 121(18): 3435-3444, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36045575

RESUMO

We study the chemotaxis of a population of genetically identical swimming bacteria undergoing run and tumble dynamics driven by stochastic switching between clockwise and counterclockwise rotation of the flagellar rotary system, where the steady-state rate of the switching changes in different environments. Understanding chemotaxis quantitatively requires that one links the measured steady-state switching rates of the rotary system, as well as the directional changes of individual swimming bacteria in a gradient of chemoattractant/repellant, to the efficiency of a population of bacteria in moving up/down the gradient. Here we achieve this by using a probabilistic model, parametrized with our experimental data, and show that the response of a population to the gradient is complex. We find the changes to the steady-state switching rate in the absence of gradients affect the average speed of the swimming bacterial population response as well as the width of the distribution. Both must be taken into account when optimizing the overall response of the population in complex environments.


Assuntos
Flagelos , Corrida , Bactérias , Fatores Quimiotáticos , Quimiotaxia/fisiologia , Flagelos/fisiologia , Modelos Biológicos , Natação
4.
J Neuroimmunol ; 371: 577929, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35939944

RESUMO

BACKGROUND: Microglia are involved in many neurodegenerative diseases and repairment of traumatic injury to the CNS. Activin A is a neurotrophic and neuroprotective factor that can regulate the activities of macrophages/microglia. However, the effects of activin A on the migration of microglia are still unclear. In this study, the role of activin A in regulation of the microglia migration was investigated with the murine microglial BV2 cell. METHODS: The levels of cytokines were detected by enzyme-linked immunosorbent assay (ELISA). The protein expression was examined by Western blotting. The adhesion of BV2 cells was assayed by real-time cell analysis (RTCA). The migration of BV2 cells was determined by transwell chamber and microfluidics device. Smad3 was overexpressed or knocked down in BV2 cells by transfection of Smad3 or Smad3 shRNA-expressing plasmids. RESULTS: Activin A inhibited the release of nitric oxide (NO) and inflammatory cytokines of TNF-α and IL-6 and the expression of TNF-α and IL-6 mRNA by BV2 cells. In contrast, activin A promoted the production of TGF-ß1. Activin A inhibited adhesion, promoted wound healing and migration which is related to the expression of N-cadherin and E-cadherin expression. Additionally, Smad3 overexpression in BV2 cells decreased the levels of TNF-α and IL-6, and promoted the wound healing, whereas Smad3 knockdown showed the opposite effects. CONCLUSIONS: These findings revealed that activin A regulated the biological behavior of BV2 cells via Smad3 signaling, suggesting that activin A may serve as a potential treatment target for neuroinflammation and glia scar formation in nervous system.


Assuntos
Microglia , Fator de Necrose Tumoral alfa , Ativinas , Animais , Fatores Quimiotáticos , Citocinas/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Nat Commun ; 13(1): 4653, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35970835

RESUMO

Parasitic plants are worldwide threats that damage major agricultural crops. To initiate infection, parasitic plants have developed the ability to locate hosts and grow towards them. This ability, called host tropism, is critical for parasite survival, but its underlying mechanism remains mostly unresolved. To characterise host tropism, we used the model facultative root parasite Phtheirospermum japonicum, a member of the Orobanchaceae. Here, we show that strigolactones (SLs) function as host-derived chemoattractants. Chemotropism to SLs is also found in Striga hermonthica, a parasitic member of the Orobanchaceae, but not in non-parasites. Intriguingly, chemotropism to SLs in P. japonicum is attenuated in ammonium ion-rich conditions, where SLs are perceived, but the resulting asymmetrical accumulation of the auxin transporter PIN2 is diminished. P. japonicum encodes putative receptors that sense exogenous SLs, whereas expression of a dominant-negative form reduces its chemotropic ability. We propose a function for SLs as navigators for parasite roots.


Assuntos
Orobanchaceae , Parasitos , Animais , Fatores Quimiotáticos/metabolismo , Produtos Agrícolas/metabolismo , Compostos Heterocíclicos com 3 Anéis , Lactonas/metabolismo , Orobanchaceae/metabolismo , Parasitos/metabolismo , Raízes de Plantas/metabolismo , Tropismo Viral
6.
J Cell Sci ; 135(16)2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35916164

RESUMO

The Dictyostelium atypical mitogen-activated protein kinase (MAPK) Erk2 is required for chemotactic responses to cAMP as amoeba undergo multicellular development. In this study, Erk2 was found to be essential for the cAMP-stimulated translocation of the GATA transcription factor GtaC as indicated by the distribution of a GFP-GtaC reporter. Erk2 was also found to be essential for the translocation of GtaC in response to external folate, a foraging signal that directs the chemotaxis of amoeba to bacteria. Erk1, the only other Dictyostelium MAPK, was not required for the GtaC translocation to either chemoattractant, indicating that GFP-GtaC is a kinase translocation reporter specific for atypical MAPKs. The translocation of GFP-GtaC in response to folate was absent in mutants lacking the folate receptor Far1 or the coupled G-protein subunit Gα4. Loss of GtaC function resulted in enhanced chemotactic movement to folate, suggesting that GtaC suppresses responses to folate. The alteration of four Erk2-preferred phosphorylation sites in GtaC impacted the translocation of GFP-GtaC in response to folate and the GFP-GtaC-mediated rescue of aggregation and development of gtaC- cells. The ability of different chemoattractants to stimulate Erk2-regulated GtaC translocation suggests that atypical MAPK-mediated regulation of transcription factors can contribute to different cell fates.


Assuntos
Dictyostelium , Fatores Quimiotáticos/metabolismo , Fatores Quimiotáticos/farmacologia , Dictyostelium/metabolismo , Ácido Fólico/farmacologia , Fatores de Transcrição GATA/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo
7.
Medicine (Baltimore) ; 101(29): e29638, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35866785

RESUMO

RATIONALE: Amyloidogenic leukocyte chemotactic factor 2 (ALECT2) was recently considered as a new clinicopathologic type of amyloid, which frequently affects kidney in adults and results in different degrees of renal insufficiency and failure with or without proteinuria. Here, we present a case of combining LECT2-associated renal amyloidosis with immunoglobulin (Ig)A nephropathy. PATIENT CONCERNS: A 71-year-old Chinese man presented with edema of both lower extremities. DIAGNOSES: There was pale eosinophilic material strongly positive for the Congo red stain in interstitium with demonstrated apple green birefringence under polarized light. Immunofluorescent stain was positive for IgA deposits (4+), IgG deposits (2+), C3 deposits (3+) within the mesangium and capillary wall. Immunohistochemistry was positive for κ (+), λ (2+) in mesangial area, and LECT2 (2+) in the interstitium. On electron microscopy, there were electron-dense deposits within mesangial area and subendothelial and randomly orientated and nonbranching fibrils 10 nm in size found in the interstitium areas. Liquid chromatography tandem mass spectrometry was performed on peptides extracted from Congo red-positive, microdissected areas of the paraffin-embedded kidney specimen. LECT 2-associated renal amyloidosis with IgA nephropathy was pathologically confirmed by renal biopsy. INTERVENTIONS: Steroids (60 mg/d) were used to treat IgA nephropathy daily. Antihypertensive treatment was switched to an angiotensin-converting enzyme inhibitor. OUTCOMES: One year after diagnosis, creatine remained stable in the normal range, and 24-hour proteinuria decreased to 2.9 g. LESSONS: To date, ALECT2 has still not been comprehensively investigated. The findings of this research provide insights for concurrent IgA nephropathy with ALECT2.


Assuntos
Amiloidose , Glomerulonefrite por IGA , Adulto , Idoso , Amiloidose/complicações , Amiloidose/diagnóstico , Amiloidose/patologia , Antígenos CD8 , Fatores Quimiotáticos , Vermelho Congo , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Rim/patologia , Leucócitos/patologia , Masculino , Proteinúria/patologia
8.
Lab Chip ; 22(17): 3203-3216, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-35856590

RESUMO

Chemotaxis is a fundamental bacterial response mechanism to changes in chemical gradients of specific molecules known as chemoattractant or chemorepellent. The advancement of biological platforms for bacterial chemotaxis research is of significant interest for a wide range of biological and environmental studies. Many microfluidic devices have been developed for its study, but challenges still remain that can obscure analysis. For example, cell migration can be compromised by flow-induced shear stress, and bacterial motility can be impaired by nonspecific cell adhesion to microchannels. Also, devices can be complicated, expensive, and hard to assemble. We address these issues with a three-channel microfluidic platform integrated with natural biopolymer membranes that are assembled in situ. This provides several unique attributes. First, a static, steady and robust chemoattractant gradient was generated and maintained. Second, because the assembly incorporates assembly pillars, the assembled membrane arrays connecting nearby pillars can be created longer than the viewing window, enabling a wide 2D area for study. Third, the in situ assembled biopolymer membranes minimize pressure and/or chemiosmotic gradients that could induce flow and obscure chemotaxis study. Finally, nonspecific cell adhesion is avoided by priming the polydimethylsiloxane (PDMS) microchannel surfaces with Pluronic F-127. We demonstrated chemotactic migration of Escherichia coli as well as Pseudomonas aeruginosa under well-controlled easy-to-assemble glucose gradients. We characterized motility using the chemotaxis partition coefficient (CPC) and chemotaxis migration coefficient (CMC) and found our results consistent with other reports. Further, random walk trajectories of individual cells in simple bright field images were conveniently tracked and presented in rose plots. Velocities were calculated, again in agreement with previous literature. We believe the biopolymer membrane-integrated platform represents a facile and convenient system for robust quantitative assessment of cellular motility in response to various chemical cues.


Assuntos
Quimiotaxia , Técnicas Analíticas Microfluídicas , Biopolímeros , Fatores Quimiotáticos , Quimiotaxia/fisiologia , Escherichia coli/fisiologia , Microfluídica
9.
Proc Natl Acad Sci U S A ; 119(31): e2201249119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35878025

RESUMO

The bacteria-derived formyl peptide fMet-Leu-Phe (fMLF) is a potent chemoattractant of phagocytes that induces chemotaxis at subnanomolar concentrations. At higher concentrations, fMLF inhibits chemotaxis while stimulating degranulation and superoxide production, allowing phagocytes to kill invading bacteria. How an agonist activates distinct cellular functions at different concentrations remains unclear. Using a bioluminescence resonance energy transfer-based FPR1 biosensor, we found that fMLF at subnanomolar and micromolar concentrations induced distinct conformational changes in FPR1, a Gi-coupled chemoattractant receptor that activates various phagocyte functions. Neutrophil-like HL-60 cells exposed to subnanomolar concentrations of fMLF polarized rapidly and migrated along a chemoattractant concentration gradient. These cells also developed an intracellular Ca2+ concentration gradient. In comparison, high nanomolar and micromolar concentrations of fMLF triggered the PLC-ß/diacyl glycerol/inositol trisphosphate pathway downstream of the heterotrimeric Gi proteins, leading to Ca2+ mobilization from intracellular stores and Ca2+ influx from extracellular milieu. A robust and uniform rise in cytoplasmic Ca2+ level was required for degranulation and superoxide production but disrupted cytoplasmic Ca2+ concentration gradient and inhibited chemotaxis. In addition, elevated ERK1/2 phosphorylation and ß-arrestin2 membrane translocation were associated with diminished chemotaxis in the presence of fMLF above 1 nM. These findings suggest a mechanism for FPR1 agonist concentration-dependent signaling that leads to a switch from migration to bactericidal activities in phagocytes.


Assuntos
Neutrófilos , Fagócitos , Receptores de Formil Peptídeo , Superóxidos , Cálcio/metabolismo , Fatores Quimiotáticos/metabolismo , Quimiotaxia , Células HL-60 , Humanos , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/fisiologia , Fagócitos/fisiologia , Receptores de Formil Peptídeo/metabolismo , Superóxidos/metabolismo
10.
J Cell Biol ; 221(8)2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35856919

RESUMO

Reading, interpreting and crawling along gradients of chemotactic cues is one of the most complex questions in cell biology. In this issue, Georgantzoglou et al. (2022. J. Cell. Biol.https://doi.org/10.1083/jcb.202103207) use in vivo models to map the temporal sequence of how neutrophils respond to an acutely arising gradient of chemoattractant.


Assuntos
Fatores Quimiotáticos , Quimiotaxia , Neutrófilos , Fatores Quimiotáticos/química , Neutrófilos/citologia
11.
Cell Commun Signal ; 20(1): 94, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35715847

RESUMO

BACKGROUND: Chemoattractant is critical to recruitment of osteoclast precursors and stimulates tumor bone metastasis. However, the role of chemoattractant in bone metastasis of colorectal cancer (CRC) is still unclear. METHODS: Histochemistry analysis and TRAP staining were utilized to detect the bone resorption and activation of osteoclasts (OCs) after administration of CCL7 neutralizing antibody or CCR1 siRNA. qRT-PCR analysis and ELISA assay were performed to detect the mRNA level and protein level of chemoattractant. BrdU assay and Tunel assay were used to detect the proliferation and apoptosis of osteoclast precursors (OCPs). The migration of OCPs was detected by Transwell assay. Western blots assay was performed to examine the protein levels of pathways regulating the expression of CCL7 or CCR1. RESULTS: OCPs-derived CCL7 was significantly upregulated in bone marrow after bone metastasis of CRC. Blockage of CCL7 efficiently prevented bone resorption. Administration of CCL7 promoted the migration of OCPs. Lactate promoted the expression of CCL7 through JNK pathway. In addition, CCR1 was the most important receptor of CCL7. CONCLUSION: Our study indicates the essential role of CCL7-CCR1 signaling for recruitment of OCPs in early bone metastasis of CRC. Targeting CCL7 or CCR1 could restore the bone volume, which could be a potential therapeutical target. Video Abstract.


Assuntos
Neoplasias Ósseas , Quimiocina CCL7 , Neoplasias Colorretais , Osteoclastos , Osteólise , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Quimiocina CCL7/metabolismo , Fatores Quimiotáticos/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Osteoclastos/patologia , Osteólise/metabolismo , Regulação para Cima
12.
Nat Cell Biol ; 24(7): 1019-1028, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35739317

RESUMO

Neutrophils migrating towards chemoattractant gradients amplify their recruitment range by releasing the secondary chemoattractant leukotriene B4 (LTB4) refs. 1,2. We previously demonstrated that LTB4 and its synthesizing enzymes, 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP) and leukotriene A4 hydrolase, are packaged and released in exosomes3. Here we report that the biogenesis of the LTB4-containing exosomes originates at the nuclear envelope (NE) of activated neutrophils. We show that the neutral sphingomyelinase 1 (nSMase1)-mediated generation of ceramide-enriched lipid-ordered microdomains initiates the clustering of the LTB4-synthesizing enzymes on the NE. We isolated and analysed exosomes from activated neutrophils and established that the FLAP/5-LO-positive exosome population is distinct from that of the CD63-positive exosome population. Furthermore, we observed a strong co-localization between ALIX and FLAP at the periphery of nuclei and within cytosolic vesicles. We propose that the initiation of NE curvature and bud formation is mediated by nSMase1-dependent ceramide generation, which leads to FLAP and ALIX recruitment. Together, these observations elucidate the mechanism for LTB4 secretion and identify a non-conventional pathway for exosome generation.


Assuntos
Exossomos , Proteínas Ativadoras de 5-Lipoxigenase , Ceramidas/metabolismo , Fatores Quimiotáticos/metabolismo , Exossomos/metabolismo , Leucotrieno B4/metabolismo , Neutrófilos/metabolismo , Membrana Nuclear/metabolismo
13.
Biophys J ; 121(13): 2557-2567, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35644945

RESUMO

Cell migration on an adhesive substrate surface comprises actin-based protrusion at the front and retraction of the tail in combination with coordinated adhesion to, and detachment from, the substrate. To study the effect of cell-to-substrate adhesion on the chemotactic response of Dictyostelium discoideum cells, we exposed the cells to patterned substrate surfaces consisting of adhesive and inert areas, and forced them by a gradient of chemoattractant to enter the border between the two areas. Wild-type as well as myosin II-deficient cells stop at the border of an adhesive area. They do not detach with their rear part, while on the nonadhesive area they protrude pseudopods at their front toward the source of chemoattractant. Avoidance of the nonadhesive area may cause a cell to move in tangential direction relative to the attractant gradient, keeping its tail at the border of the adhesive surface.


Assuntos
Dictyostelium , Actinas/metabolismo , Movimento Celular/fisiologia , Fatores Quimiotáticos/farmacologia , Quimiotaxia , Miosina Tipo II/metabolismo , Pseudópodes/metabolismo
14.
J Cell Mol Med ; 26(13): 3598-3607, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35656863

RESUMO

LECT2 (leucocyte cell-derived chemotaxin 2) is a 16-kDa protein mainly produced by hepatocytes. It was first isolated in PHA-activated human T-cell leukaemia SKW-3 cells and originally identified as a novel neutrophil chemotactic factor. However, many lines of studies suggested that LECT2 was a pleiotropic protein, it not only functioned as a cytokine to exhibit chemotactic property, but also played multifunctional roles in some physiological conditions and pathological abnormalities, involving liver regeneration, neuronal development, HSC(haematopoietic stem cells) homeostasis, liver injury, liver fibrosis, hepatocellular carcinoma, metabolic disorders, inflammatory arthritides, systemic sepsis and systemic amyloidosis. Among the above studies, it was discovered that LECT2 could be a promising molecular biomarker and therapeutic target. This review summarizes LECT2-related receptors and pathways, basic and clinical researches, primarily in mice and human, for a better comprehension and management of these diseases in the future.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Fatores Quimiotáticos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos
15.
Expert Opin Biol Ther ; 22(7): 883-893, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35668707

RESUMO

INTRODUCTION: Tissue engineering has brought hope for the repair of bone and cartilage injury. As potential therapeutic molecules for use in tissue engineering, chemokines promote the development of cell-free tissue engineering, avoiding dilemmas faced by cell-based tissue engineering. The main role of chemokines in tissue engineering is to recruit progenitor/stem cells to the site of damaged tissue in vivo and induce differentiation into the corresponding tissue, thus remodeling tissue function. In recent years, many studies have demonstrated the great potential of chemokines in the regeneration and repair of various tissues, such as heart, bone and cartilage tissue. AREAS COVERED: The classification, structure, and function of chemokines and the application of several common chemokines in diseases, especially in bone/cartilage tissue regeneration are discussed. EXPERT OPINION: Many studies have demonstrated that the combinatory use of cell chemotactic factors (CCFs) and growth factors can exert synergistic effects on chondrogenesis and osteogenesis. With further understanding of biomaterials and the development of powerful bio-fabrication techniques, intelligent biomaterials will be created to meet the requirements for controlled bioactive factor release and biomimetic architecture. Also, a better understanding of the biological cascade reactions and pathways of CCFs is beneficial to guide the design of innovative biomaterials.


Assuntos
Fatores Quimiotáticos , Engenharia Tecidual , Materiais Biocompatíveis/química , Cartilagem , Diferenciação Celular , Condrogênese , Humanos , Osteogênese , Engenharia Tecidual/métodos , Tecidos Suporte/química
16.
Elife ; 112022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666122

RESUMO

In order to migrate over large distances, cells within tissues and organisms rely on sensing local gradient cues which are irregular, conflicting, and changing over time and space. The mechanism how they generate persistent directional migration when signals are disrupted, while still remaining adaptive to signal's localization changes remain unknown. Here, we find that single cells utilize a molecular mechanism akin to a working memory to satisfy these two opposing demands. We derive theoretically that this is characteristic for receptor networks maintained away from steady states. Time-resolved live-cell imaging of Epidermal growth factor receptor (EGFR) phosphorylation dynamics shows that cells transiently memorize position of encountered signals via slow-escaping remnant of the polarized signaling state, a dynamical 'ghost', driving memory-guided persistent directional migration. The metastability of this state further enables migrational adaptation when encountering new signals. We thus identify basic mechanism of real-time computations underlying cellular navigation in changing chemoattractant fields.


If we are injured, or fighting an infection, cells in our body migrate over large distances to the site of the wound or infection to act against any invading microbes or repair the damage. Cells navigate to the damaged site by sensing local chemical cues, which are irregular, conflicting and change over time and space. This implies that cells can choose which direction to travel, and stick to it even if the signals around them are disrupted, while still retaining the ability to alter their direction if the location of the signal changes. However, how cells are able to effectively navigate their way through this field of complex chemical cues is poorly understood. To help resolve this mystery, Nandan, Das et al. studied the epidermal growth factor receptor (EGFR) signaling network which controls how some cells in the body change shape and migrate. The network is activated by specific chemical cues, or ligands, binding to EGFR proteins on the cell surface. The receptors then join together to form pairs, and several tags known as phosphate groups are added to each molecule. This process (known as phosphorylation) switches the receptor pair to an active state, allowing EGFR to relay signals to other proteins in the cell and promote the activity of receptors not bound to a ligand. The phosphorylation state of EGFRs is then modulated over time and across the cell by a network of enzymes called phosphatases which can remove the phosphate groups and switch off the receptor. To study EGFR phosphorylation dynamics in human cells, Nandan, Das et al. imaged individual cells over time using a microscope. This data was then combined with a mathematical model describing the EGFR signaling network and how cells change their shape over time. The experiment revealed that the phosphate groups attached to EGFR are not removed immediately when the chemical cue is gone. Instead, the active state is transiently maintained before complete inactivation. This had the effect of encoding a short-lived memory in the signaling network that allowed the cells to continue to migrate in a certain direction even when chemical cues were disrupted. This memory state is dynamic, enabling cells to adapt direction when the cue changes location. The findings of Nandan, Das et al. reveal the underlying mechanism for how cells decipher complex chemical cues to migrate to where they are needed most. The next steps to follow on from this work will be to understand if other receptors involved in migration work in a similar way.


Assuntos
Fatores Quimiotáticos , Memória de Curto Prazo , Fosforilação , Transdução de Sinais
17.
PLoS Comput Biol ; 18(5): e1010089, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35584137

RESUMO

The motility of neutrophils and their ability to sense and to react to chemoattractants in their environment are of central importance for the innate immunity. Neutrophils are guided towards sites of inflammation following the activation of G-protein coupled chemoattractant receptors such as CXCR2 whose signaling strongly depends on the activity of Ca2+ permeable TRPC6 channels. It is the aim of this study to analyze data sets obtained in vitro (murine neutrophils) and in vivo (zebrafish neutrophils) with a stochastic mathematical model to gain deeper insight into the underlying mechanisms. The model is based on the analysis of trajectories of individual neutrophils. Bayesian data analysis, including the covariances of positions for fractional Brownian motion as well as for exponentially and power-law tempered model variants, allows the estimation of parameters and model selection. Our model-based analysis reveals that wildtype neutrophils show pure superdiffusive fractional Brownian motion. This so-called anomalous dynamics is characterized by temporal long-range correlations for the movement into the direction of the chemotactic CXCL1 gradient. Pure superdiffusion is absent vertically to this gradient. This points to an asymmetric 'memory' of the migratory machinery, which is found both in vitro and in vivo. CXCR2 blockade and TRPC6-knockout cause tempering of temporal correlations in the chemotactic gradient. This can be interpreted as a progressive loss of memory, which leads to a marked reduction of chemotaxis and search efficiency of neutrophils. In summary, our findings indicate that spatially differential regulation of anomalous dynamics appears to play a central role in guiding efficient chemotactic behavior.


Assuntos
Quimiotaxia , Neutrófilos , Animais , Teorema de Bayes , Fatores Quimiotáticos , Quimiotaxia/fisiologia , Camundongos , Canal de Cátion TRPC6 , Peixe-Zebra
18.
Chem Senses ; 472022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35580574

RESUMO

Toxic puffers accumulate their defense substance (tetrodotoxin; TTX) through the food chain. Although the previous study suggests that 5,6,11-trideoxyTTX, a nontoxic TTX analog detected simultaneously with TTX in toxic puffers or their prey, acts as an olfactory chemoattractant for grass puffers, it is unclear whether toxic puffers are commonly attracted to 5,6,11-trideoxyTTX, and which types of olfactory sensory neurons (OSNs) detect 5,6,11-trideoxyTTX. Here, we demonstrated that green spotted puffer, a phylogenetically distant species from the grass puffer, is attracted to 5,6,11-trideoxyTTX. 5,6,11-TrideoxyTTX administration made green spotted puffers stay longer at the administered site, whereas a food odor (l-Arg) made them actively swim throughout the aquarium. Attractive responses were not observed when TTX or its vehicle was administered, nor when 5,6,11-trideoxyTTX was administered to anosmic fish. Furthermore, double immunohistochemistry with activity marker and crypt OSN marker antibodies labeled oval cells with apical invagination on the olfactory epithelium surface treated with 5,6,11-trideoxyTTX. These results suggest that 5,6,11-trideoxyTTX acts as an olfactory chemoattractant detected by crypt OSNs, and attraction to 5,6,11-trideoxyTTX odor appears to be a trait shared by toxic puffers for social communication or effective toxification.


Assuntos
Neurônios Receptores Olfatórios , Tetraodontiformes , Animais , Fatores Quimiotáticos , Odorantes , Mucosa Olfatória , Tetrodotoxina/química , Tetrodotoxina/farmacologia
19.
Exp Cell Res ; 418(1): 113218, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35618013

RESUMO

Interplay between models and experimental data advances discovery and understanding in biology, particularly when models generate predictions that allow well-designed experiments to distinguish between alternative mechanisms. To illustrate how this feedback between models and experiments can lead to key insights into biological mechanisms, we explore three examples from cellular slime mold chemotaxis. These examples include studies that identified chemotaxis as the primary mechanism behind slime mold aggregation, discovered that cells likely measure chemoattractant gradients by sensing concentration differences across cell length, and tested the role of cell-associated chemoattractant degradation in shaping chemotactic fields. Although each study used a different model class appropriate to their hypotheses - qualitative, mathematical, or simulation-based - these examples all highlight the utility of modeling to formalize assumptions and generate testable predictions. A central element of this framework is the iterative use of models and experiments, specifically: matching experimental designs to the models, revising models based on mismatches with experimental data, and validating critical model assumptions and predictions with experiments. We advocate for continued use of this interplay between models and experiments to advance biological discovery.


Assuntos
Dictyosteliida , Dictyostelium , Fatores Quimiotáticos/farmacologia , Quimiotaxia , Simulação por Computador , Modelos Biológicos
20.
J Vis Exp ; (181)2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35404349

RESUMO

Chemotaxis identification is very important for the research and application of rhizosphere growth-promoting bacteria. We established a straightforward method to quickly identify the chemoattractants that could induce the chemotactic movement of rhizosphere growth-promoting bacteria on sterile glass slides via simple steps. Bacteria solution (OD600 = 0.5) and sterile chemoattractant aqueous solution were added dropwise on the glass slide at an interval of 1 cm. An inoculating loop was used to connect the chemoattractant aqueous solution to the bacterial solution. The slide was kept at room temperature for 20 min on the clean bench. Finally, the chemoattractant aqueous solution was collected for bacterial counting and microscopic observation. In this study, through multiple comparisons of experimental results, the method overcame multiple shortcomings of traditional bacterial chemotaxis methods. The method reduced the error of plate counting and shortened the experimental cycle. For the identification of chemoattractant substances, this new method can save 2-3 days compared to the traditional method. Additionally, this method allows any researcher to systematically complete a bacterial chemotaxis experiment within 1-2 days. The protocol can be considered a valuable resource for understanding plant-microbe interactions.


Assuntos
Fatores Quimiotáticos , Quimiotaxia , Bactérias , Fatores Quimiotáticos/farmacologia , Exsudatos e Transudatos , Raízes de Plantas/microbiologia
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