scholarly journals Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology

2019 ◽  
Vol 116 (27) ◽  
pp. 13490-13497 ◽  
Author(s):  
Saba Nayar ◽  
Joana Campos ◽  
Charlotte G. Smith ◽  
Valentina Iannizzotto ◽  
David H. Gardner ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Functional Role ◽  
Functional Requirements ◽  
Local Production ◽  
Functional Changes ◽  
Molecular Programming ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

scholarly journals Tertiary Lymphoid Structures and Cancer Prognosis (Brief Review)

2020 ◽  
Vol 9 (4) ◽  
pp. 293-296
Author(s):  
R. A. Rustamkhanov ◽  
K. Sh. Gantsev ◽  
D. S. Tursumetov
Keyword(s):  
Pathological Process ◽  
Cancer Prognosis ◽  
Oncological Diseases ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Available Information ◽  
The Relationship ◽  
Shed Light

This brief review is devoted to the role of tertiary lymphoid structures in oncological processes. A number of research studies carried out over the past ten years have shed light on the functions of such structures in various diseases, as well as their role in the progression of the pathological process or resolution of a disease. The data presented in some research works confirms the relationship between the presence of tumour-specific (tumour-associated) tertiary lymphoid structures and a favourable prognosis in patients with various oncological diseases, which suggests the participation of tertiary lymphoid structures in effective local antitumour immune responses. However, no reliable evidence has so far been obtained that could confirm the contribution of tertiary lymphoid structures to immune processes in vivo, with the available information being largely of a correlative character. It should be emphasized that the clinical significance of tertiary lymphoid structures ranges from a destructive to protective impact, which indicates the need for an improved understanding of the structure and case-specific function of these organs before conducting clinical targeting.

scholarly journals WNT-5A regulates TGF-β-related activities in liver fibrosis

2017 ◽  
Vol 312 (3) ◽  
pp. G219-G227 ◽  
Author(s):  
Leonie Beljaars ◽  
Sara Daliri ◽  
Christa Dijkhuizen ◽  
Klaas Poelstra ◽  
Reinoud Gosens
Keyword(s):  
Liver Fibrosis ◽  
Functional Role ◽  
Collagen Type ◽  
Collagen Type I ◽  
Matrix Proteins ◽  
Type I ◽  
Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

scholarly journals Cathepsin G-dependent platelet stimulation by activated polymorphonuclear leukocytes and its inhibition by antiproteinases: role of P-selectin-mediated cell-cell adhesion

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2947-2957 ◽  
Author(s):  
V Evangelista ◽  
P Piccardoni ◽  
JG White ◽  
G de Gaetano ◽  
C Cerletti
Keyword(s):  
Functional Role ◽  
Polymorphonuclear Leukocytes ◽  
Platelet Adhesion ◽  
Inhibitory Effect ◽  
Serotonin Release ◽  
Cathepsin G ◽  
Inhibitory Antibody ◽  
Neuraminidase Treatment

Human PMN stimulated by fMLP are able to activate coincubated, autologous platelets. Cathepsin G, a neutral serine protease stored in the azurophilic granules of PMN, is the major platelet activator in this system. We previously proposed that shear-induced close PMN- platelet contact creates the conditions for which cathepsin G activity on platelets is protected against antiproteinases. The aim of this study was to investigate the adhesive mechanisms, possibly creating between PMN and platelet membranes the microenvironment in which cathepsin G, discharged from stimulated PMN onto adherent platelets, is protected against antiproteinases. Microscopic examination showed that under conditions of high shear, 71.3% +/- 6.1% of PMN were associated to platelets forming small clumps. This percentage decreased to 10% +/- 2% and 13% +/- 4%, respectively, in the presence of an inhibitory antibody to P-selectin or 20 mmol/L mannose-1-phosphate and to 10.8% +/- 3.7% when cells were not stirred. Similarly, PMN pretreatment with neuraminidase abolished PMN binding to platelets. These results indicate that P-selectin mediates PMN-platelet adhesion occurring before PMN stimulation. Prevention of PMN-platelet contact significantly potentiated the inhibitory effect of alpha 1-protease inhibitor on subsequent cathepsin G-induced platelet serotonin release. Because anti-P-selectin antibody, mannose-1-phosphate, and neuraminidase treatment of PMN did not modify PMN-induced platelet activation in the absence of antiproteinases, it is suggested that P- selectin-mediated PMN-platelet adhesion results in the formation of a sequestered microenvironment between cell membranes, in which higher amounts of antiproteinases are required to prevent the activity of released cathepsin G. These data add a new functional role to P- selectin-mediated PMN-platelet adhesion that could be important in vivo because of the presence of antiproteinases in plasma.

Exploring the Role of Tertiary Lymphoid Structures Using a Mouse Model of Bacteria-Infected Lungs

2018 ◽  
pp. 223-239 ◽  
Author(s):  
Jean-Luc Teillaud ◽  
Lucile Regard ◽  
Clémence Martin ◽  
Sophie Sibéril ◽  
Pierre-Régis Burgel
Keyword(s):  
Mouse Model ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Contribution of R domain phosphoserines to the function of CFTR studied in Fischer rat thyroid epithelia

2000 ◽  
Vol 279 (5) ◽  
pp. L835-L841 ◽  
Author(s):  
Olafur Baldursson ◽  
Herbert A. Berger ◽  
Michael J. Welsh
Keyword(s):  
Functional Role ◽  
Transmembrane Conductance Regulator ◽  
Regulatory Domain ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Dependent Protein ◽  
Rat Thyroid ◽  
Cystic Fibrosis Transmembrane

The regulatory domain of cystic fibrosis transmembrane conductance regulator (CFTR) regulates channel activity when several serines are phosphorylated by cAMP-dependent protein kinase. To further define the functional role of individual phosphoserines, we studied CFTR containing previously studied and new serine to alanine mutations. We expressed these constructs in Fischer rat thyroid epithelia and measured transepithelial Cl− current. Mutation of four in vivo phosphorylation sites, Ser660, Ser737, Ser795, and Ser813 (S-Quad-A), substantially decreased cAMP-stimulated current, suggesting that these four sites account for most of the phosphorylation-dependent response. Mutation of either Ser660 or Ser813 alone significantly decreased current, indicating that these residues play a key role in phosphorylation-dependent stimulation. However, neither Ser660 nor Ser813 alone increased current to wild-type levels; both residues were required. Changing Ser737 to alanine increased current above wild-type levels, suggesting that phosphorylation of Ser737 may inhibit current in wild-type CFTR. These data help define the functional role of regulatory domain phosphoserines and suggest interactions between individual phosphoserines.

scholarly journals Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 587 ◽  
Author(s):  
Matilda Munksgaard Thorén ◽  
Katarzyna Chmielarska Masoumi ◽  
Cecilia Krona ◽  
Xiaoli Huang ◽  
Soumi Kundu ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Target ◽  
Functional Role ◽  
Treatment Strategies ◽  
Antibody Drug Conjugate ◽  
Potential Therapeutic Target ◽  
Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

Identifying the Functional Role of Martinotti Cells in Cortical Sensory Processing

2009 ◽  
Vol 102 (1) ◽  
pp. 9-11 ◽  
Author(s):  
James C. H. Cottam
Keyword(s):  
Sensory Processing ◽  
Pyramidal Cell ◽  
Functional Significance ◽  
Functional Role ◽  
Neural Computation ◽  
Inhibitory Interneurons ◽  
Local Circuit ◽  
Processing Function

Inhibitory interneurons are highly diverse, although the functional significance of their diversity is not yet well understood. This presents a barrier to understanding neural computation at the local circuit level. This review focuses on a recent study by Murayama et al. who used a novel in vivo technique in neocortex to demonstrate a specific sensory processing function of dendritic-targeting Martinotti interneurons. The function of Martinotti cells arises from their interaction with layer 5 pyramidal cell dendrites.

scholarly journals Dissecting the Prognostic Significance and Functional Role of Progranulin in Chronic Lymphocytic Leukemia

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 822 ◽  
Author(s):  
Lena Schulze-Edinghausen ◽  
Claudia Dürr ◽  
Selcen Öztürk ◽  
Manuela Zucknick ◽  
Axel Benner ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Cancer Associated Fibroblast ◽  
Survival Gene ◽  
Potential Use

Chronic lymphocytic leukemia (CLL) is known for its strong dependency on the tumor microenvironment. We found progranulin (GRN), a protein that has been linked to inflammation and cancer, to be upregulated in the serum of CLL patients compared to healthy controls, and increased GRN levels to be associated with an increased hazard for disease progression and death. This raised the question of whether GRN is a functional driver of CLL. We observed that recombinant GRN did not directly affect viability, activation, or proliferation of primary CLL cells in vitro. However, GRN secretion was induced in co-cultures of CLL cells with stromal cells that enhanced CLL cell survival. Gene expression profiling and protein analyses revealed that primary mesenchymal stromal cells (MSCs) in co-culture with CLL cells acquire a cancer-associated fibroblast-like phenotype. Despite its upregulation in the co-cultures, GRN treatment of MSCs did not mimic this effect. To test the relevance of GRN for CLL in vivo, we made use of the Eμ-TCL1 CLL mouse model. As we detected strong GRN expression in myeloid cells, we performed adoptive transfer of Eμ-TCL1 leukemia cells to bone marrow chimeric Grn−/− mice that lack GRN in hematopoietic cells. Thereby, we observed that CLL-like disease developed comparable in Grn−/− chimeras and respective control mice. In conclusion, serum GRN is found to be strongly upregulated in CLL, which indicates potential use as a prognostic marker, but there is no evidence that elevated GRN functionally drives the disease.

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