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1.
Sci Rep ; 13(1): 15632, 2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37730901

RESUMO

Ligilactobacillus agilis is a motile lactic acid bacterium found in the gastrointestinal tracts of animals. The findings of our previous study suggest that the motility of L. agilis BKN88 enables gut colonization in murine models. However, the chemotactic abilities of motile lactobacilli remain unknown. This study aimed to identify the gut-derived chemoeffectors and their corresponding chemoreceptors in L. agilis BKN88. Chemotaxis assays with chemotactic and non-chemotactic (ΔcheA) L. agilis strains revealed that low pH, organic acids, and bile salts served as repellents. L. agilis BKN88 was more sensitive to bile and acid than the gut-derived non-motile lactobacilli, implying that L. agilis might utilize motility and chemotaxis instead of exhibiting stress tolerance/resistance. L. agilis BKN88 contains five putative chemoreceptor genes (mcp1-mcp5). Chemotaxis assays using a series of chemoreceptor mutants revealed that each of the five chemoreceptors could sense multiple chemoeffectors and that these chemoreceptors were functionally redundant. Mcp2 and Mcp3 sensed all tested chemoeffectors. This study provides further insights into the interactions between chemoreceptors and ligands of motile lactobacilli and the unique ecological and evolutionary features of motile lactobacilli, which may be distinct from those of non-motile lactobacilli.


Assuntos
Células Quimiorreceptoras , Quimiotaxia , Animais , Camundongos , Ácidos e Sais Biliares/farmacologia , Evolução Biológica
2.
Nat Commun ; 14(1): 5584, 2023 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-37696800

RESUMO

Spatial heterogeneity in antibiotic concentrations is thought to accelerate the evolution of antibiotic resistance, but current theory and experiments have overlooked the effect of cell motility on bacterial adaptation. Here, we study bacterial evolution in antibiotic landscapes with a quantitative model where bacteria evolve under the stochastic processes of proliferation, death, mutation and migration. Numerical and analytical results show that cell motility can both accelerate and decelerate bacterial adaptation by affecting the degree of genotypic mixing and ecological competition. Moreover, we find that for sufficiently high rates, cell motility can limit bacterial survival, and we derive conditions for all these regimes. Similar patterns are observed in more complex scenarios, namely where bacteria can bias their motion in chemical gradients (chemotaxis) or switch between motility phenotypes either stochastically or in a density-dependent manner. Overall, our work reveals limits to bacterial adaptation in antibiotic landscapes that are set by cell motility.


Assuntos
Aclimatação , Antibacterianos , Antibacterianos/farmacologia , Bactérias/genética , Quimiotaxia , Resistência Microbiana a Medicamentos/genética
3.
Int J Mol Sci ; 24(17)2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37686390

RESUMO

The loss of vitamin D3 upregulated protein 1 (VDUP1) has been implicated in the pathogenesis of various inflammation-related diseases. Notably, reduced expression of VDUP1 has been observed in clinical specimens of ulcerative colitis (UC). However, the role of VDUP1 deficiency in colitis remains unclear. In this study, we investigated the role of VDUP1 in dextran sulfate sodium (DSS)-induced experimental colitis in mice. VDUP1-deficient mice were more susceptible to DSS-induced colitis than their wild-type (WT) littermates after 2% DSS administration. VDUP1-deficient mice exhibited an increased disease activity index (DAI) and histological scores, as well as significant colonic goblet cell loss and an increase in apoptotic cells. These changes were accompanied by a significant decrease in MUC2 mRNA expression and a marked increase in proinflammatory cytokines and chemokines within damaged tissues. Furthermore, phosphorylated NF-κB p65 expression was significantly upregulated in damaged tissues in the context of VDUP1 deficiency. VDUP1 deficiency also led to significant infiltration of macrophages into the site of ulceration. An in vitro chemotaxis assay confirmed that VDUP1 deficiency enhanced bone marrow-derived macrophage (BMDM) chemotaxis induced by CCL2. Overall, this study highlights VDUP1 as a regulator of UC pathogenesis and a potential target for the future development of therapeutic strategies.


Assuntos
Colite Ulcerativa , Colite , Animais , Camundongos , Quimiotaxia , Colite/induzido quimicamente , Colite/genética , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Macrófagos
4.
Front Immunol ; 14: 1223539, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37680635

RESUMO

Background: Numerous lines of evidence confirm that decidual stromal cells (DSCs) play a key role in maternal-fetal immune tolerance. Under the influence of progesterone and other hormones, the DSCs go through a process of differentiation (decidualization) during normal pregnancy. In mice, DSCs inhibit the expression of chemokines that attract abortigenic Th1 and Tc cells to the decidua. We have studied this phenomenon in humans. Methods: We established human DSC lines and decidualized these cells in vitro with progesterone and cAMP. We determined the expression of the chemokines CXCL9, CXCL10 and CXCL11, whose receptor CXCR3 is expressed by Th1 and Tc cells, in undifferentiated DSCs and decidualized DSCs by qRT-PCR. Activated CD3+CXCR3+ cells, including CD4+ Th1 cells and CD8+ Tc cells, were induced in vitro. The migration capacity of these activated lymphocytes was investigated in Transwell chambers with conditioned media from undifferentiated and decidualized DSCs. Results: We demonstrated that CXCL9 was not expressed by DSCs, whereas the expression of CXCL10 and CXCL11 was inhibited in decidualized cells. Conditioned media from decidualized cells significantly inhibited the migration of Th1 and Tc cells. We found that decidualized cells secrete factors of MW less than 6000-8000 Da, which actively inhibit the chemotaxis of these lymphocytes. Discussion: These results confirm in humans that decidualization of DSCs inhibits the expression by these cells of chemokines that attract Th1 and Tc cells and induces the secretion by DSCs of factors that inhibit the chemotaxis of these lymphocytes, thus preventing the arrival of abortigenic T cells in the decidua.


Assuntos
Quimiotaxia , Progesterona , Feminino , Gravidez , Humanos , Animais , Camundongos , Meios de Cultivo Condicionados , Feto , Linfócitos T CD8-Positivos
5.
J R Soc Interface ; 20(206): 20230279, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37700707

RESUMO

Neuronal circuits are hallmarks of complex decision-making processes in the animal world. How animals without neurons process information and respond to environmental cues promises a new window into studying precursors of neuronal control and origin of the nervous system as we know it today. Robust decision making in animals, such as in chemotaxis or thermotaxis, often requires internal symmetry breaking (such as anterior-posterior (AP) axis) provided naturally by a given body plan of an animal. Here we report the discovery of robust thermotaxis behaviour in Trichoplax adhaerens, an early-divergent, enigmatic animal with no anterior-posterior symmetry breaking (apolar) and no known neurons or muscles. We present a quantitative and robust behavioural response assay in Placozoa, which presents an apolar flat geometry. By exposing T. adhaerens to a thermal gradient under a long-term imaging set-up, we observe robust thermotaxis that occurs over timescale of hours, independent of any circadian rhythms. We quantify that T. adhaerens can detect thermal gradients of at least 0.1°C cm-1. Positive thermotaxis is observed for a range of baseline temperatures from 17°C to 22.5°C, and distributions of momentary speeds for both thermotaxis and control conditions are well described by single exponential fits. Interestingly, the organism does not maintain a fixed orientation while performing thermotaxis. Using natural diversity in size of adult organisms (100 µm to a few millimetres), we find no apparent size-dependence in thermotaxis behaviour across an order of magnitude of organism size. Several transient receptor potential (TRP) family homologues have been previously reported to be conserved in metazoans, including in T. adhaerens. We discover naringenin, a known TRPM3 antagonist, inhibits thermotaxis in T. adhaerens. The discovery of robust thermotaxis in T. adhaerens provides a tractable handle to interrogate information processing in a brainless animal. Understanding how divergent marine animals process thermal cues is also critical due to rapid temperature rise in our oceans.


Assuntos
Neurônios , Resposta Táctica , Animais , Quimiotaxia , Ritmo Circadiano , Cognição
6.
PLoS Genet ; 19(9): e1010637, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37669262

RESUMO

The nematode Caenorhabditis elegans memorizes various external chemicals, such as ions and odorants, during feeding. Here we find that C. elegans is attracted to the monosaccharides glucose and fructose after exposure to these monosaccharides in the presence of food; however, it avoids them without conditioning. The attraction to glucose requires a gustatory neuron called ASEL. ASEL activity increases when glucose concentration decreases. Optogenetic ASEL stimulation promotes forward movements; however, after glucose conditioning, it promotes turning, suggesting that after glucose conditioning, the behavioral output of ASEL activation switches toward glucose. We previously reported that chemotaxis toward sodium ion (Na+), which is sensed by ASEL, increases after Na+ conditioning in the presence of food. Interestingly, glucose conditioning decreases Na+ chemotaxis, and conversely, Na+ conditioning decreases glucose chemotaxis, suggesting the reciprocal inhibition of learned chemotaxis to distinct chemicals. The activation of PKC-1, an nPKC ε/η ortholog, in ASEL promotes glucose chemotaxis and decreases Na+ chemotaxis after glucose conditioning. Furthermore, genetic screening identified ENSA-1, an ortholog of the protein phosphatase inhibitor ARPP-16/19, which functions in parallel with PKC-1 in glucose-induced chemotactic learning toward distinct chemicals. These findings suggest that kinase-phosphatase signaling regulates the balance between learned behaviors based on glucose conditioning in ASEL, which might contribute to migration toward chemical compositions where the animals were previously fed.


Assuntos
Caenorhabditis elegans , Açúcares , Animais , Caenorhabditis elegans/genética , Quimiotaxia , Cloreto de Sódio , Glucose/farmacologia , Monossacarídeos
7.
Curr Biol ; 33(18): R957-R959, 2023 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-37751709

RESUMO

A new study reports that dendritic cells actively shape the CCL19 chemokine gradient to which they respond and that the chemokine receptor CCR7 both senses CCL19 and mediates its internalisation. Generation of local changes in chemokines allows coordination of movement over longer distances than previous models could explain.


Assuntos
Quimiotaxia , Mecanismos de Defesa , Movimento , Imunidade , Células Dendríticas
8.
J Biol Dyn ; 17(1): 2260833, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37756309

RESUMO

Chemotaxis is a directed cell movement in response to external chemical stimuli. In this paper, we propose a simple model for the origin of chemotaxis - namely how a directed movement in response to an external chemical signal may occur based on purely reaction-diffusion equations reflecting inner working of the cells. The model is inspired by the well-studied role of the rho-GTPase Cdc42 regulator of cell polarity, in particular in yeast cells. We analyse several versions of the model to better understand its analytic properties and prove global regularity in one and two dimensions. Using computer simulations, we demonstrate that in the framework of this model, at least in certain parameter regimes, the speed of the directed movement appears to be proportional to the size of the gradient of signalling chemical. This coincides with the form of the chemical drift in the most studied mean field model of chemotaxis, the Keller-Segel equation.


Assuntos
Quimiotaxia , Modelos Biológicos , Simulação por Computador , Difusão , Movimento
9.
J Alzheimers Dis ; 95(2): 549-559, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37574731

RESUMO

BACKGROUND: Neuroinflammation is one of the cardinal mechanisms of Alzheimer's disease (AD). with amyloid-ß (Aß) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aß species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. OBJECTIVE: We aimed to evaluate the role of the oligomeric Aß1-42 isoform at inducing peripheral monocyte chemotaxis, and the possible involvement of TSPO in this process. METHODS: In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n = 60), and comparable cognitively intact controls (n = 30) were used. Chemotaxis analyses were carried out through both µ-slide chambers and Boyden assays, using 125 pM oligomeric Aß1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). RESULTS: Oligomeric Aß directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aß-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. CONCLUSION: Oligomeric Aß1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS.


Assuntos
Doença de Alzheimer , Humanos , Monócitos/metabolismo , Quimiotaxia , Doenças Neuroinflamatórias , Peptídeos beta-Amiloides/farmacologia , Peptídeos beta-Amiloides/metabolismo , Receptores de GABA/metabolismo
10.
Soft Matter ; 19(34): 6446-6457, 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37606542

RESUMO

We report a two-layer microfluidic device to study the combined effect of confinement and chemical gradient on the motility of wild-type E. coli. We track individual E. coli in 50 µm and 10 µm wide microchannels, with a channel height of 2 µm, to generate quasi-2D conditions. We find that contrary to expectations, bacterial trajectories are superdiffusive even in the absence of a chemical (glucose) gradient. The superdiffusive behaviour becomes more pronounced upon introducing a chemical gradient or strengthening the lateral confinement. Run length distributions for weak lateral confinement in the absence of chemical gradients follow an exponential distribution. Both confinement and chemoattraction induce deviations from this behaviour, with the run length distributions approaching a power-law form under these conditions. Both confinement and chemoattraction suppress large-angle tumbles as well. Our results suggest that wild-type E. coli modulates both its runs and tumbles in a similar manner under physical confinement and chemical gradient. Our findings have implications for understanding how bacteria modulate their motility behaviour in natural habitats.


Assuntos
Escherichia coli , Microfluídica , Escherichia coli/genética , Quimiotaxia , Difusão , Glucose
11.
Proc Natl Acad Sci U S A ; 120(35): e2303814120, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37603754

RESUMO

Neutrophil recruitment to sites of infection and inflammation is an essential process in the early innate immune response. Upon activation, a subset of neutrophils rapidly assembles the multiprotein complex known as the NLRP3 inflammasome. The NLRP3 inflammasome forms at the microtubule organizing center, which promotes the formation of interleukin (IL)-1ß and IL-18, essential cytokines in the immune response. We recently showed that mice deficient in NLRP3 (NLRP3-/-) have reduced neutrophil recruitment to the peritoneum in a model of thioglycolate-induced peritonitis. Here, we tested the hypothesis that this diminished recruitment could be, in part, the result of defects in neutrophil chemotaxis. We find that NLRP3-/- neutrophils show loss of cell polarization, as well as reduced directionality and velocity of migration toward increasing concentrations of leukotriene B4 (LTB4) in a chemotaxis assay in vitro, which was confirmed through intravital microscopy of neutrophil migration toward a laser-induced burn injury of the liver. Furthermore, pharmacologically blocking NLRP3 inflammasome assembly with MCC950 in vitro reduced directionality but preserved nondirectional movement, indicating that inflammasome assembly is specifically required for polarization and directional chemotaxis, but not cell motility per se. In support of this, pharmacological breakdown of the microtubule cytoskeleton via nocodazole treatment induced cell polarization and restored nondirectional cell migration in NLRP3-deficient neutrophils in the LTB4 gradient. Therefore, NLRP3 inflammasome assembly is required for establishment of cell polarity to guide the directional chemotactic migration of neutrophils.


Assuntos
Quimiotaxia , Leucotrieno B4 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Camundongos , Inflamassomos , Leucotrieno B4/metabolismo , Neutrófilos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
12.
ACS Nano ; 17(17): 17285-17298, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37595091

RESUMO

Tumor interstitial pressure represents the greatest barrier against drug diffusion into the depth of the tumor. Biometric nanomotors highlight the possibility of enhanced deep penetration and improve cellular uptake. However, control of their directionality remains difficult to achieve. Herein, we report cysteine-arginine-glutamic acid-lysine-alanine (CREKA)-modified ceria@polydopamine nanobowls as tumor microenvironment-fueled nanoscale motors for positive chemotaxis into the tumor depth or toward tumor cells. Upon laser irradiation, this nanoswimmer rapidly depletes the tumor microenvironment-specific hydrogen peroxide (H2O2) in the nanobowl, contributing to a self-generated gradient and subsequently propulsion (9.5 µm/s at 46 °C). Moreover, the asymmetrical modification of CREKA on nanobowls could automatically reconfigure the motion direction toward tumor depth or tumor cells in response to receptor-ligand interaction, leading to a deep penetration (70 µm in multicellular spheroids) and enhanced antitumor effects over conventional nanomedicine-induced chemo-photothermal therapy (tumor growth inhibition rate: 84.2% versus 56.9%). Thus, controlling the direction of nanomotors holds considerable potential for improved antitumor responses, especially in solid tumors with high tumor interstitial pressure.


Assuntos
Quimiotaxia , Neoplasias , Humanos , Biomimética , Peróxido de Hidrogênio , Terapia Fototérmica , Microambiente Tumoral
13.
J Neurochem ; 166(6): 891-903, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37603311

RESUMO

Microglia maintain brain homeostasis through their ability to survey and phagocytose danger-associated molecular patterns (DAMPs). In Alzheimer's disease (AD), microglial phagocytic clearance regulates the turnover of neurotoxic DAMPs including amyloid beta (Aß) and hyperphosphorylated tau. To mediate DAMP clearance, microglia express a repertoire of surface receptors to sense DAMPs; the activation of these receptors subsequently triggers a chemotaxis-to-phagocytosis functional transition in microglia. Therefore, the interaction between microglial receptors and DAMPs plays a critical role in controlling microglial DAMP clearance and AD pathogenesis. However, there is no comprehensive overview on how microglial sensome receptors interact with DAMPs and regulate various microglial functions, including chemotaxis and phagocytosis. In this review, we discuss the important axes of receptor-ligand interaction that control different microglial functions and their roles in AD pathogenesis. First, we summarize how the accumulation and structural changes of DAMPs trigger microglial functional impairment, including impaired DAMP clearance and aberrant synaptic pruning, in AD. Then, we discuss the important receptor-ligand axes that restore microglial DAMP clearance in AD and aging. These findings suggest that targeting microglial chemotaxis-the first critical step of the microglial chemotaxis-to-phagocytosis state transition-can promote microglial DAMP clearance in AD. Thus, our review highlights the importance of microglial chemotaxis in promoting microglial clearance activity in AD. Further detailed investigations are essential to identify the molecular machinery that controls microglial chemotaxis in AD.


Assuntos
Doença de Alzheimer , Humanos , Microglia , Peptídeos beta-Amiloides , Quimiotaxia , Ligantes
14.
Curr Biol ; 33(18): 3835-3850.e6, 2023 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-37591249

RESUMO

Studies of neuronal connectivity in model organisms, i.e., of their connectomes, have been instrumental in dissecting the structure-function relationship of nervous systems. However, the limited sample size of these studies has impeded analyses into how variation of connectivity across populations may influence circuit architecture and behavior. Moreover, little is known about how experiences induce changes in circuit architecture. Here, we show that an asymmetric salt-sensing circuit in the nematode Caenorhabditis elegans exhibits variation that predicts the animals' salt preferences and undergoes restructuring during salt associative learning. Naive worms memorize and prefer the salt concentration they experience in the presence of food through a left-biased neural network architecture. However, animals conditioned at elevated salt concentrations change this left-biased network to a right-biased network. This change in circuit architecture occurs through the addition of new synapses in response to asymmetric, paracrine insulin signaling. Therefore, experience-dependent changes in an animal's neural connectome are induced by insulin signaling and are fundamental to learning and behavior.


Assuntos
Proteínas de Caenorhabditis elegans , Animais , Proteínas de Caenorhabditis elegans/fisiologia , Insulina , Quimiotaxia/fisiologia , Caenorhabditis elegans/fisiologia , Sinapses , Cloreto de Sódio
15.
Int J Oncol ; 63(4)2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37615176

RESUMO

Collective cellular invasion in malignant tumours is typically characterized by the cooperative migration of multiple cells in close proximity to each other. Follower cells are led away from the tumour by specialized leader cells, and both cell populations play a crucial role in collective invasion. Follower cells form the main body of the migration system and depend on intercellular contact for migration, whereas leader cells indicate the direction for the entire cell population. Although collective invasion can occur in epithelial and non­epithelial malignant neoplasms, such as medulloblastoma and rhabdomyosarcoma, the present review mainly provided an extensive analysis of epithelial tumours. In the present review, the cooperative mechanisms of contact inhibition locomotion between follower and leader cells, where follower cells coordinate and direct collective movement through physical (mechanical) and chemical (signalling) interactions, is summarised. In addition, the molecular mechanisms of follower cell invasion and metastasis during remodelling and degradation of the extracellular matrix and how chemotaxis and lateral inhibition mediate follower cell behaviour were analysed. It was also demonstrated that follower cells exhibit genetic and metabolic heterogeneity during invasion, unlike leader cells.


Assuntos
Carcinoma , Neoplasias Cerebelares , Humanos , Comunicação Celular , Diferenciação Celular , Quimiotaxia
16.
Proc Natl Acad Sci U S A ; 120(34): e2301873120, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37579142

RESUMO

Bacteria navigate natural habitats with a wide range of mechanical properties, from the ocean to the digestive tract and soil, by rotating helical flagella like propellers. Species differ in the number, position, and shape of their flagella, but the adaptive value of these flagellar architectures is unclear. Many species traverse multiple types of environments, such as pathogens inside and outside a host. We investigate the hypothesis that flagellar architectures mediate environment-specific benefits in the marine pathogen Vibrio alginolyticus which exhibits physiological adaptation to the mechanical environment. In addition to its single polar flagellum, the bacterium produces lateral flagella in environments that differ mechanically from water. These are known to facilitate surface motility and attachment. We use high-throughput 3D bacterial tracking to quantify chemotactic performance of both flagellar architectures in three archetypes of mechanical environments relevant to the bacterium's native habitats: water, polymer solutions, and hydrogels. We reveal that lateral flagella impede chemotaxis in water by lowering the swimming speed but improve chemotaxis in both types of complex environments. Statistical trajectory analysis reveals two distinct underlying behavioral mechanisms: In viscous solutions of the polymer PVP K90, lateral flagella increase the swimming speed. In agar hydrogels, lateral flagella improve overall chemotactic performance, despite lowering the swimming speed, by preventing trapping in pores. Our findings show that lateral flagella are multipurpose tools with a wide range of applications beyond surfaces. They implicate flagellar architecture as a mediator of environment-specific benefits and point to a rich space of bacterial navigation behaviors in complex environments.


Assuntos
Quimiotaxia , Vibrio alginolyticus , Bactérias , Flagelos/fisiologia , Adaptação Fisiológica , Proteínas de Bactérias
17.
Cancer Immunol Immunother ; 72(10): 3363-3376, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37525065

RESUMO

Polymorphonuclear neutrophils (PMNs) are the main effector cells in the inflammatory response. The significance of PMN infiltration in the tumor microenvironment remains unclear. Metastatic melanoma is the most lethal skin cancer with an increasing incidence over the last few decades. This study aimed to investigate the role of PMNs and their related mediators in human melanoma. Highly purified human PMNs from healthy donors were stimulated in vitro with conditioned media (CM) derived from the melanoma cell lines SKMEL28 and A375 (melanoma CM), and primary melanocytes as controls. PMN biological properties (chemotaxis, survival, activation, cell tracking, morphology and NET release) were evaluated. We found that the A375 cell line produced soluble factors that promoted PMN chemotaxis, survival, activation and modification of morphological changes and kinetic properties. Furthermore, in both melanoma cell lines CM induced chemotaxis, activation and release of neutrophil extracellular traps (NETs) from PMNs. In contrast, the primary melanocyte CM did not modify the biological behavior of PMNs. In addition, serum levels of myeloperoxidase, matrix metalloprotease-9, CXCL8/IL-8, granulocyte and monocyte colony-stimulating factor and NETs were significantly increased in patients with advanced melanoma compared to healthy controls. Melanoma cell lines produce soluble factors able to "educate" PMNs toward an activated functional state. Patients with metastatic melanoma display increased circulating levels of neutrophil-related mediators and NETs. Further investigations are needed to better understand the role of these "tumor-educated neutrophils" in modifying melanoma cell behavior.


Assuntos
Armadilhas Extracelulares , Melanoma , Humanos , Neutrófilos/patologia , Quimiotaxia , Melanoma/patologia , Microambiente Tumoral
18.
Theranostics ; 13(11): 3856-3871, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37441587

RESUMO

Rationale: Liver ischemia-reperfusion (LI/R) injury is characterized by two interconnected phases: local ischemia that causes hepatic cell damage to release damage-associated molecular pattern (DAMPs), and DAMPs that recruit immune cells to elicit inflammatory cascade for further injury of hepatocytes. High-mobility group box 1 (HMGB1) is a representative DAMP. Studies in macrophages demonstrated that HMGB1 is secreted after lactylation during sepsis. However, whether lactylation mediates HMGB1 secretion from hepatocytes after LI/R is known. Heat shock protein A12A (HSPA12A) is an atypical member of HSP70 family. Methods: Gene expression was examined by microarray analysis and immunoblotting. The hepatic injury was analyzed using released ALT and AST activities assays. Hepatic macrophage chemotaxis was evaluated by Transwell chemotaxis assays. Inflammatory mediators were evaluated by immunoblotting. HMGB1 secretion was examined in exosomes or serum. HMGB1 lactylation was determined using immunoprecipitation and immunoblotting. Results: Here, we report that LI/R decreased HSPA12A expression in hepatocytes, while hepatocyte-specific HSPA12A overexpression attenuated LI/R-induced hepatic dysfunction and mortality of mice. We also noticed that hepatocyte HSPA12A overexpression suppressed macrophage chemotaxis to LI/R-exposed livers in vivo and to hypoxia/reoxygenation (H/R)-exposed hepatocytes in vitro. The LI/R-increased serum HMGB1 levels of mice and the H/R-increased HMGB1 lactylation and secretion levels of hepatocytes were also inhibited by hepatocyte HSPA12A overexpression. By contrast, HSPA12A knockout in hepatocytes promoted not only H/R-induced HMGB1 lactylation and secretion of hepatocytes but also the effects of H/R-hepatocytes on macrophage chemotaxis and inflammatory activation, while all these deleterious effects of HSPA12A knockout were reversed following hepatocyte HMGB1 knockdown. Further molecular analyses showed that HSPA12A overexpression reduced glycolysis-generated lactate, thus decreasing HMGB1 lactylation and secretion from hepatocytes, thereby inhibiting not only macrophage chemotaxis but also the subsequent inflammatory cascade, which ultimately protecting against LI/R injury. Conclusion: Taken together, these findings suggest that hepatocyte HSPA12A is a novel regulator that protects livers from LI/R injury by suppressing glycolysis-mediated HMGB1 lactylation and secretion from hepatocytes to inhibit macrophage chemotaxis and inflammatory activation. Therefore, targeting hepatocyte HSPA12A may have therapeutic potential in the management of LI/R injury in patients.


Assuntos
Proteína HMGB1 , Hepatopatias , Traumatismo por Reperfusão , Animais , Camundongos , Proteínas de Choque Térmico/metabolismo , Proteína HMGB1/metabolismo , Quimiotaxia , Fígado/metabolismo , Hepatócitos/metabolismo , Macrófagos/metabolismo , Glicólise , Traumatismo por Reperfusão/metabolismo , Camundongos Endogâmicos C57BL
19.
Elife ; 122023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37489570

RESUMO

Olfactory navigation is observed across species and plays a crucial role in locating resources for survival. In the laboratory, understanding the behavioral strategies and neural circuits underlying odor-taxis requires a detailed understanding of the animal's sensory environment. For small model organisms like Caenorhabditis elegans and larval Drosophila melanogaster, controlling and measuring the odor environment experienced by the animal can be challenging, especially for airborne odors, which are subject to subtle effects from airflow, temperature variation, and from the odor's adhesion, adsorption, or reemission. Here, we present a method to control and measure airborne odor concentration in an arena compatible with an agar substrate. Our method allows continuous controlling and monitoring of the odor profile while imaging animal behavior. We construct stationary chemical landscapes in an odor flow chamber through spatially patterned odorized air. The odor concentration is measured with a spatially distributed array of digital gas sensors. Careful placement of the sensors allows the odor concentration across the arena to be continuously inferred in space and monitored through time. We use this approach to measure the odor concentration that each animal experiences as it undergoes chemotaxis behavior and report chemotaxis strategies for C. elegans and D. melanogaster larvae populations as they navigate spatial odor landscapes.


Assuntos
Drosophila melanogaster , Odorantes , Animais , Caenorhabditis elegans , Olfato , Quimiotaxia , Comportamento Animal
20.
Cell Struct Funct ; 48(2): 145-160, 2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37438131

RESUMO

In eukaryotic motile cells, the active Ras (Ras-GTP)-enriched domain is generated in an asymmetric manner on the cell membrane through the excitable dynamics of an intracellular signaling network. This asymmetric Ras signaling regulates pseudopod formation for both spontaneous random migration and chemoattractant-induced directional migration. While membrane lipids, such as sphingomyelin and phosphatidylserine, contribute to Ras signaling in various cell types, whether they are involved in the Ras excitability for cell motility is unknown. Here we report that functional Ras excitability requires the normal metabolism of sphingomyelin for efficient cell motility and chemotaxis. The pharmacological blockade of sphingomyelin metabolism by an acid-sphingomyelinase inhibitor, fendiline, and other inhibitors suppressed the excitable generation of the stable Ras-GTP-enriched domain. The suppressed excitability failed to invoke enough basal motility to achieve directed migration under shallow chemoattractant gradients. The fendiline-induced defects in Ras excitability, motility and stimulation-elicited directionality were due to an accumulation of sphingomyelin on the membrane, which could be recovered by exogenous sphingomyelinase or phosphatidylserine without changing the expression of Ras. These results indicate a novel regulatory mechanism of the excitable system by membrane lipids, in which sphingomyelin metabolism provides a membrane environment to ensure Ras excitation for efficient cellular motility and chemotaxis.Key words: cell polarity, cell migration, Ras, excitability, sphingomyelin.


Assuntos
Quimiotaxia , Esfingomielinas , Quimiotaxia/fisiologia , Esfingomielina Fosfodiesterase/metabolismo , Fosfatidilserinas , Fendilina , Movimento Celular , Fatores Quimiotáticos , Guanosina Trifosfato
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