New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

Huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare reagent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical reagents.

ADHESION CONCEPT IN CANCER BIOLOGY: LOCAL AND CENTRAL MECHANISMS (PART 1)

The review presents the concept the key mechanism of the tumor process is a violation of adhesion interactions involving local and central mechanisms. Local features of adhesive dysregulation are demonstrated in the first part. The lack of histospecific adhesion molecules expression resulting from stress or genetic mutation damages an important mechanism of antitumor protection of the tissue disrupting the processes of proliferation and differentiation. The deficiency of histone-specific homotypic adhesion molecules which occurs later exacerbates the disorders. This leads to a decrease in the expression of leukocyte integrins (LFA-1, Mac-1) ligands of the β2 family on the surface of immune effectors and to an increase also in the expression of adhesion molecules to the substrate-antigens VLA (very late activation) family of β1 -integrins on tumor cells. The first restricts the interaction of ICAM family molecules with their contra-receptors from the β2 -integrin family reducing the elimination of target cells by immune effectors which contributes to the screening of the tumor from antitumor surveillance. The second promotes the invasion of the tumor into the surrounding tissues, the formation of blood vessels as well as its heterotypic adhesion with other tissues which further stimulates the proliferation and suppression processes of tumor cells apoptosis. So, the adhesion molecules can be compared to the Phoenix bird: disappearing at the beginning of the process (between the similar cells), they reappear in a new quality (increasing adhesion to cells of other tissues), increasing the totalysm of the tumor. It should be taken into account that tumor cells due to adhesion dysregulation “isolate themselves from society”, lose their differentiation, their maturity and “fall into childhood”, being unable to perform specific, “adult” functions. So, cancer can be considered as a manifestation of the cells aging. Therefore, the anti-stress, endogenous geroprotective mechanisms activation based on the adhesion correction can be effective for preventing and treatment the oncological process.

New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin

Integrin α4β1 belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization of new peptidomimetic compounds that are potentially able to recognize α4β1 integrin and interfere with its function. To this aim, a collection of seven new cyclic peptidomimetics possessing both a 4-aminoproline (Amp) core scaffold grafted onto key α4β1-recognizing sequences and the (2-methylphenyl)ureido-phenylacetyl (MPUPA) appendage, was designed, with the support of molecular modeling studies. The new compounds were synthesized through SPPS procedures followed by in-solution cyclization maneuvers. The biological evaluation of the new cyclic ligands in cell adhesion assays on Jurkat cells revealed promising submicromolar agonist activity in one compound, namely, the c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds.

Expression and Pathogenic Analysis of Integrin Family Genes in Systemic Sclerosis

Objectives: Emerging evidence shows that integrin members are involved in inflammation and fibrosis in systemic sclerosis (SSc). This study aimed at evaluating the expression of integrin family genes in the skin tissue from SSc patients and exploring the potential pathogenic mechanism.Methods: We utilized the public datasets of SSc skin tissue from the Gene Expression Omnibus (GEO) database to analyze the expression and clinical significance of integrin family genes in SSc. The expression of integrin members in skin tissue was also assessed by immunohistochemistry. In addition, functional enrichment and pathway analysis were conducted.Results: Compared with healthy controls, the mRNA and protein levels of ITGA5, ITGB2, and ITGB5 were upregulated in the skin of SSc patients. Further analysis indicated that the mRNA expression levels of ITGA5, ITGB2, and ITGB5 were positively correlated with modified Rodnan skin thickness score (mRSS). Functional enrichment and pathway analysis showed that integrin members may play multiple roles in the pathogenesis of SSc. Among them, ITGA5, ITGB2, and ITGB5 might synergistically promote SSc through affecting extracellular matrix (ECM) turnover, ECM–receptor interaction, focal adhesion, and leukocyte trans-endothelial migration, while ITGA5 and ITGB5 also might affect angiogenesis and endothelial cell function. In addition, ITGA5, ITGB2, and ITGA5 were associated with different pathways, respectively. ITGA5 was uniquely enriched for actin organization, while ITGB5 was for TGF-β signaling and ITGB2 for immune cell activation.Conclusion: Our results implied that the abnormal expression of integrin family genes including ITGA5, ITGB2, and ITGB5 may participate in multiple pathological processes in SSc. Further investigations are required for confirming this speculation.

α2β1 integrins spatially restrict Cdc42 activity to stabilise adherens junctions

Background Keratinocytes form the main protective barrier in the skin to separate the underlying tissue from the external environment. In order to maintain this barrier, keratinocytes form robust junctions between neighbouring cells as well as with the underlying extracellular matrix. Cell–cell adhesions are mediated primarily through cadherin receptors, whereas the integrin family of transmembrane receptors is predominantly associated with assembly of matrix adhesions. Integrins have been shown to also localise to cell–cell adhesions, but their role at these sites remains unclear. Results Here we show that α2β1 integrins are enriched at mature keratinocyte cell–cell adhesions, where they play a crucial role in organising cytoskeletal networks to stabilize adherens junctions. Loss of α2β1 integrin has significant functional phenotypes associated with cell–cell adhesion destabilisation, including increased proliferation, reduced migration and impaired barrier function. Mechanistically, we show that α2β1 integrins suppress activity of Src and Shp2 at cell–cell adhesions leading to enhanced Cdc42–GDI interactions and stabilisation of junctions between neighbouring epithelial cells. Conclusion Our data reveals a new role for α2β1 integrins in controlling integrity of epithelial cell–cell adhesions.

β2 integrin activation and signaling transduction in leukocyte recruitment

Leukocyte recruitment is a critical step in the pathogenesis of inflammatory and immunological responses. Cell adhesion molecules (CAMs) are involved in controlling cell movements and the recruitment process, and the integrin family of CAMs plays a key role. During cell movement, integrin function is dynamically and precisely regulated. However, this balance might be broken under pathological conditions. Thus, the functional regulation and molecular mechanisms of integrins related to diseases are often a focus of research. Integrin β2 is one of the most commonly expressed integrins in leukocytes that mediates leukocyte adhesion and migration, and it plays an important role in immune responses and inflammation. In this review, we focus on specific functions of integrin β2 in leukocyte recruitment, the conformational changes and signal transduction of integrin β2 activation, and how new insights into these processes can inform future therapies for inflammation and immune diseases.

AB0095 EXPRESSION AND PATHOGENIC ROLES OF INTEGRIN FAMILY GENE IN SYSTEMIC SCLEROSIS

Background:Emerging evidence have shown that some integrin members are associated with inflammation and fibrosis in systemic sclerosis (SSc) patients[1-2]. However, the expression patterns and pathogenic significance of the whole integrin family in SSc are still unclear.Objectives:This study aimed at evaluating the integrin family gene expression in skin lesion from SSc patients and exploring its potential pathogenic mechanism.Methods:We utilized the public datasets of SSc skin tissue from Gene Expression Omnibus (GEO) database to analyze the expression and clinical significance of integrin family genes in SSc. In addition, functional enrichment and pathway analysis were also conducted.Results:Compared with healthy controls, ITGA5, ITGA7, ITGA8, ITGB2, ITGB5, ITGAE and ITGB3BP were abnormally overexpressed in the skin of SSc. Further analysis indicated that ITGA5, ITGA7, ITGA8, ITGB2 and ITGB5 were positively correlated with modified Rodnan skin thickness score (mRSS), while ITGAE and ITGB3BP were negatively correlated with mRSS in SSc. Increased ITGB5 expression was associated with positive of anti-centromere antibody (ACA). Functional enrichment and pathway analysis showed that integrin members had multiple functions in SSc. Among them, ITGA5, ITGB2 and ITGB5 might synergistically promote SSc through affecting extracellular matrix (ECM) turn over, ECM-receptor interaction, focal adhesion and leukocyte trans-endothelial migration. ITGA5 and ITGB5 also affected angiogenesis and endothelial cell function. In addition, ITGA5 was uniquely enriched for actin organization, ITGB5 was uniquely enriched for TGF-β signaling, and ITGB2 was uniquely associated with immune cells activation.Conclusion:Our results implied that integrins, especially ITGA5, ITGB5, ITGB2 participated in the process of inflammation, vasculopathy and fibrosis in SSc. Together, they might render important therapeutic targets for SSc.References:[1]Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. 2019;195(3):310-321.[2]Gerber, E.E., et al., Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature, 2013. 503(7474): p. 126-30.Disclosure of Interests:None declared

Integrin-α9β1 as a Novel Therapeutic Target for Refractory Diseases: Recent Progress and Insights

Integrins refer to heterodimers consisting of subunits α and β. They serve as receptors on cell membranes and interact with extracellular ligands to mediate intracellular molecular signals. One of the least-studied members of the integrin family is integrin-α9β1, which is widely distributed in various human tissues and organs. Integrin-α9β1 regulates the physiological state of cells through a variety of complex signaling pathways to participate in the specific pathological processes of some intractable diseases. In recent years, an increasing amount of research has focused on the role of α9β1 in the molecular mechanisms of different refractory diseases and its promising potential as a therapeutic target. Accordingly, this review introduces and summarizes recent research related to integrin-α9β1, describes the synergistic functions of α9β1 and its corresponding ligands in cancer, autoimmune diseases, nerve injury and thrombosis and, more importantly, highlights the potential of α9β1 as a distinctive target for the treatment of these intractable diseases.

The progression of intracerebral hemorrhage (ICH) is related to the expression of integrin Β1 (ITGB1)

Background Intracerebral hemorrhage (ICH) is fatal and detrimental to quality of life. Clinically, options for monitoring are often limited, potentially missing subtle neurological changes. Integrin β 1 (ITGB1) and β 3 (ITGB3) are the main components of integrin family receptors, which regulate the formation and stability of blood vessels. This study explored the relationship between the expression of ITGB1 and ITGB3 in intracerebral hemorrhage (ICH) to analyze their functional and clinical relevance. Methods The expression of ITGB1 and ITGB3 in ICH was accomplished by immunohistochemical (IHC) staining and western blotting (WB) analysis, respectively. Results Furthermore, the results demonstrated that ITGB1 was expressed in ICH tissues, but ITGB3 was not expressed in ICH tissues. Conclusions In summary, the clinical progression of ICH was related to the expression of ITGB1. ITGB1 may be a potential biomarker and contribute to the treatment of ICH.