An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Suchard, Suzanne J.; Stetsko, Dawn K.; Davis, Patricia M.; Skala, Stacey; Potin, Dominique; Launay, Michèle; Dhar, T. G. Murali; Barrish, Joel C.; Susulic, Vojkan; Shuster, David J.; McIntyre, Kim W.; McKinnon, Murray; Salter–Cid, Luisa

doi:10.4049/jimmunol.0901095

Cited by 38 publications

(39 citation statements)

References 57 publications

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“…There were two key processes involved in the increasing of the blood-brain barrier permeability: the first one was loosening the tight junctions between endothelial cells, primarily used for increasing the para-cellular transport; the second one was activation of the endocytosis at the luminal surface of endothelial cells, used primarily for the increase of the transcellular transport [22]. Meanwhile, LFA-1 has been identified as an adhesion molecule in both immune and inflammatory reactions, with LFA-1 membrane molecule associated with the regulation of the adhesion between the T lymphocytes and human endothelial cells, which has been classified as the first process involved in in increasing the blood-brain barrier permeability [23]. Therefore, we came to the conclusion that LFA-1 could reduce the blood-brain barrier permeability.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Yu¹,

Li²,

Che³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cerebral ischemia is considered to be the most common cause of stroke with high mortality. It occurs as a result of the damage of the hippocampal neurons with lymphocyte function–associated antigen (LFA)-1 being emphasized to play a role in the biological functions of hippocampal neurons. This study was conducted in order to investigate the effects of specific knockdown of LFA-1 expression by lentivirus had on the apoptosis of the hippocampal neurons, simulated by rat models of acute cerebral ischemia after cerebral lymphatic blockage. Methods: A total of 60 Wistar rats were selected as subjects, among which 50 were used to establish models of the acute cerebral ischemia after cerebral lymphatic blockage, while the remaining 10 rats were treated with the sham operation. The underlying regulatory mechanisms regarding LFA-1 were analyzed with the treatment of si-LFA-1 and LFA-1 vector in the hippocampal CA1 area of brain tissues isolated from the rats with acute cerebral ischemia. The brain water content, electrolyte content, and blood-brain barrier permeability located in ischemic area of rats were measured. TUNEL staining and immunochemistry methods were employed in order to determine the apoptosis rate and positive levels of LFA-1, MMP-9, and Caspase-3. The mRNA and protein levels of related genes were also detected by means of RT-qPCR and western blot assay. Results: The brain water content, Na⁺ and Ca⁺ contents, blood-brain barrier permeability, apoptosis rate, positive levels of LFA-1, MMP-9, and Caspase-3 were decreased, and the K⁺ content was increased in ischemic tissues treated with si-LFA-1. The mRNA and protein levels of LFA-1, MMP-9, Caspase-3, and Bax had all decreased, while the mRNA and protein levels of Bcl-2 were elevated in the hippocampal CA1 area of rat brain tissues treated with si-LFA-1. These situations could be reversed through the up-regulation of LFA-1. Conclusion: In conclusion, LFA-1 gene silencing could improve the acute cerebral ischemia after cerebral lymphatic blockage by inhibiting apoptosis of the hippocampal neurons in rats.

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Section: Discussionmentioning

confidence: 99%

Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Yu¹,

Li²,

Che³

et al. 2018

Cell Physiol Biochem

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“…Interference with systemic migration of macrophages may provide a potential therapeutic treatment for the mitigation of osteolysis secondary to polyethylene wear debris. Treatment with small molecules that interfere with cell migration has been shown to have therapeutic potential in diseases such as rheumatoid arthritis [43], lymphoma [15], and other immune diseases [47]. However, biologic modulation of macrophage migration may also interfere with other important, macrophage-associated host defense mechanisms such as infection and tumor surveillance.…”

Section: Discussionmentioning

confidence: 99%

Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis

Ren

Irani

Huang

et al. 2011

Clinical Orthopaedics &Amp; Related Research

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Background Aseptic loosening and periprosthetic osteolysis resulting from wear debris are major complications of total joint arthroplasty. Monocyte/macrophages are the key cells related to osteolysis at the bone-implant interface of joint arthroplasties. Whether the monocyte/macrophages found at the implant interface in the presence of polyethylene particles are locally or systemically derived is unknown. Questions/purposes We therefore asked (1) whether macrophages associated with polyethylene particle-induced chronic inflammation are recruited locally or systemically and (2) whether the recruited macrophages are associated with enhanced osteolysis locally.Methods Noninvasive in vivo imaging techniques (bioluminescence and microCT) were used to investigate initial macrophage migration systemically from a remote injection site to polyethylene wear particles continuously infused into the femoral canal. We used histologic and immunohistologic staining to confirm localization of migrated macrophages to the polyethylene particle-treated femoral canals and monitor cellular markers of bone remodeling.Results The values for bioluminescence were increased for animals receiving UHMWPE particles compared with the group in which the carrier saline was infused. At Day 8, the ratio of bioluminescence (operated femur divided by nonoperated contralateral femur of each animal) for the UHMWPE group was 13.95 ± 5.65, whereas the ratio for the saline group was 2.60 ± 1.14. Immunohistologic analysis demonstrated the presence of reporter macrophages in the UHMWPE particle-implanted femora only. MicroCT scans showed the bone mineral density for the group with both UHMWPE particles and macrophage was lower than the control groups. Conclusions Infusion of clinically relevant polyethylene particles, similar to the human scenario, stimulated systemic migration of remotely injected macrophages and local net bone resorption.

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“…Also, the design and applicability of new LFA-1 antagonists is a potential field for therapy development [53] [59].…”

Section: Lfa-1 Participates In the Cytotoxic Immune Response Against mentioning

confidence: 99%

“…For instance, the presence of regulatory T cells, which are immunosuppressive, in the microenvironment of many solid tumors and the importance of LFA-1 in the function of these cells [52], suggests that targeting LFA-1 in these tumors would limit the function of regulatory T cells and improve the action of the immune system against the tumor [27] [28]. The acquired knowledge from targeting LFA-1 in the treatment of inflammatory diseases can be helpful here [53].…”

Section: Lfa-1 In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Role of LFA-1 and ICAM-1 in Cancer

Reina

Espel

2017

Preprint

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The lymphocyte function-associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA's role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.Keywords: cancer metastasis; chronic lymphocytic leukemia; exosomes; tumor microenvironment LFA-1 is widely expressed in hematopoietic cells, mediating intercellular interactions within the immune system and between leukocytes and non-blood cells. Several intercellular adhesion molecules (ICAM), including ICAM-1 (CD54) are common ligands for LFA-1 [1] [2]. The strength of LFA-1 adhesion varies by adjusting the affinity (conformation), the level of LFA-1 clustering and the force applied by the ligand [3] [4] [5]. LFA-1 can adopt different conformations, from a folded low-affinity inactive one to an open active conformation. The stimulation of cells by receptors like the T-cell receptor or chemokine receptors changes the adhesive properties of LFA-1 in a process called "inside-out" signaling that may open the conformation of LFA-1 and expose its ligand-binding site [6]. In addition, it should be noted that the characteristics of the external ligand binding to LFA-1 initiates a signaling cascade in LFA-1 (named "outside-in" signaling), giving rise to various cellular changes [7]. As with other integrins, LFA-1 is not a mere adhesive contact between cells, but it also mediates signals that modulate the growth, differentiation and survival of the cell. LFA-1 participates in the cytotoxic immune response against tumorsThe T cell cytotoxic response against cancer cells starts when the T cell receptor recognizes a specific tumor antigen on the surface of the cancer cell; this is normally followed by delivery of toxic granules that kill the target cell. In the cytolytic response against virus-infected cells, the adhesion between the cytotoxic lymphocyte and the target cell is not strictly dependent on LFA-1, this however is necessary in the cytolytic response to immunogenic tumors [8] [9]. LFA-1 is an essential initiator of the immunological synapse that forms between the cytotoxic T or NK cell and the cancer cell, and mediates the firm adhesion to the target cell and the polarization of cytotoxic granules towards the target [7] [10] [11]. There is a positive correlation between the maturation state of NK cells, their cytotoxic potential and the activation level of LFA-1 [12].Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by chan...

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An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Cited by 38 publications

References 57 publications

Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis

Role of LFA-1 and ICAM-1 in Cancer

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