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

Xu, Shihan; Zhang, Tingwei; Cao, Zhengguo; Zhong, Wenjie; Zhang, Chuangwei; Han, Li; Song, Jinlin

doi:10.3389/fimmu.2021.638400

Cited by 10 publications

(8 citation statements)

References 185 publications

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Section: Structure and Function Of The Integrin Familymentioning

confidence: 99%

“…96 In addition, integrin α1β9 is also involved in the regulation of cell adhesion and migration in numerous organs, such as the skin, liver, and spleen. 97 Integrin α4β7 specifically binds VCAM-1 and mucosal address in cell-adhesion molecule-1 (MAdCAM-1) to regulate lymphocyte migration, which mediates the homing of lymphocytes to gut tissues. 98,99 Collagen (GFOGER)-binding integrins Collagen-binding integrins refer to a class of integrins that bind with GFOGER-like sequences in collagen, including α1β1, α2β1, α10β1, and α11β1 100 (Fig.…”

Section: Structure and Function Of The Integrin Familymentioning

confidence: 99%

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Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

155

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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Section: Structure and Function Of The Integrin Familymentioning

confidence: 99%

Section: Structure and Function Of The Integrin Familymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

155

111

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“…Importantly, XCL1 can also act through ITGA9 ( 30 ), an extracellular matrix component, which was shown to participate in the pathophysiology of some intractable disorders by the regulation of the cell physiological state and acts through a diversity of signaling pathways. This adhesion molecule exerts a crucial function to regulate multistep processes, including migration, proliferation, and metastasis ( 31 , 53 – 55 ). Integrins consist of two subunits, α and β, so they are heterodimers.…”

Section: Discussionmentioning

confidence: 99%

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies

et al. 2022

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Recent studies have indicated the involvement of chemokine-C-motif ligand 1 (XCL1) in nociceptive transmission; however, the participation of its two receptors, canonical chemokine-C-motif receptor 1 (XCR1) and integrin alpha-9 (ITGA9), recently recognized as a second receptor, has not been clarified to date. The aim was to explore by which of these receptors XCL1 reveals its pronociceptive properties and how the XCL1-XCR1 and XCL1-ITGA9 axes blockade/neutralization influence on pain-related behavior and opioid analgesia in the model of neuropathic pain. In our studies we used Albino Swiss mice which were exposed to the unilateral sciatic nerve chronic constriction injury (CCI) as a neuropathic pain model. Animals received single intrathecal (i.t.) injection of XCL1, XCL1 neutralizing antibodies, antagonist of XCR1 (vMIP-II) and neutralizing antibodies of ITGA9 (YA4), using lumbar puncture technique. Additionally we performed i.t. co-administration of abovementioned neutralizing antibodies and antagonists with single dose of morphine/buprenorphine. To assess pain-related behavior the von Frey and cold plate tests were used. To measure mRNA and protein level the RT-qPCR and Western Blot/Elisa/immunofluorescence techniques were performed, respectively. Statistical analysis was conducted using ANOVA with a Bonferroni correction. Presented studies have shown time-dependent upregulation of the mRNA and/or protein expression of XCL1 in the spinal cord after nerve injury as measured on day 1, 4, 7, 14, and 35. Our immunofluorescence study showed that XCL1 is released by astroglial cells located in the spinal cord, despite the neural localization of its receptors. Our results also provided the first evidence that the blockade/neutralization of both receptors, XCR1 and ITGA9, reversed hypersensitivity after intrathecal XCL1 administration in naive mice; however, neutralization of ITGA9 was more effective. In addition, the results proved that the XCL1 neutralizing antibody and, similarly, the blockade of XCR1 and neutralization of ITGA9 diminished thermal and mechanical hypersensitivity in nerve injury-exposed mice after 7 days. Additionally, neutralization of XCL1 improves morphine analgesia. Moreover, blockade of XCR1 positively influences buprenorphine effectiveness, and neutralization of ITGA9 enhances not only buprenorphine but also morphine analgesia. Therefore, blockade of the XCL1-ITGA9 interaction may serve as an innovative strategy for the polypharmacotherapy of neuropathic pain in combination with opioids.

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“…In addition, α9 is known to be expressed by SMC [ 77 ], suggesting an essential role of α9 in SMC biology. In humans, α9 is encoded by the ITGA9 gene, located in the 3p21.3–22.2 segment of a chromosome, which encodes the polypeptides of 1035 amino acids and has a size of 114.5 KD [ 78 ]. The structure of α9 consists of a ligand-binding large N-terminal extracellular domain, a transmembrane segment, and a short C-terminal cytoplasmic domain that specifically binds to intracellular proteins [ 78 ].…”

Section: Integrin α9- An Overlooked Integrinmentioning

confidence: 99%

Role of Integrins in Modulating Smooth Muscle Cell Plasticity and Vascular Remodeling: From Expression to Therapeutic Implications

Jain

Chauhan

2022

Cells

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Smooth muscle cells (SMCs), present in the media layer of blood vessels, are crucial in maintaining vascular homeostasis. Upon vascular injury, SMCs show a high degree of plasticity, undergo a change from a “contractile” to a “synthetic” phenotype, and play an essential role in the pathophysiology of diseases including atherosclerosis and restenosis. Integrins are cell surface receptors, which are involved in cell-to-cell binding and cell-to-extracellular-matrix interactions. By binding to extracellular matrix components, integrins trigger intracellular signaling and regulate several of the SMC function, including proliferation, migration, and phenotypic switching. Although pharmacological approaches, including antibodies and synthetic peptides, have been effectively utilized to target integrins to limit atherosclerosis and restenosis, none has been commercialized yet. A clear understanding of how integrins modulate SMC biology is essential to facilitate the development of integrin-based interventions to combat atherosclerosis and restenosis. Herein, we highlight the importance of integrins in modulating functional properties of SMCs and their implications for vascular pathology.

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

Cited by 10 publications

References 185 publications

Targeting integrin pathways: mechanisms and advances in therapy

Targeting integrin pathways: mechanisms and advances in therapy

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies

Role of Integrins in Modulating Smooth Muscle Cell Plasticity and Vascular Remodeling: From Expression to Therapeutic Implications

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