Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program

Verma, Navin Kumar; Kelleher, Dermot

doi:10.4049/jimmunol.1700495

Cited by 86 publications

(82 citation statements)

References 111 publications

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“…In vitro pretreatment of RAW 264.7 macrophages with BIRT-377, an LFA-1 antagonist, prior to LPS stimulation results in a dose-dependent increase in IL-10 protein with a simultaneous decrease in IL-1β and TNF-α (190). Activation of LFA-1 beyond T cell interaction stimulates a variety of downstream signaling cascades in a context-dependent manner modified by the local cytokine milieu (191). In point of fact, these recent reports demonstrate in vivo proinflammatory cytokine contribution driven by activated LFA-1 on innate immune cells (e.g., macrophages) and T cells during chronic disease.…”

Section: Lymphocyte Function-associated Antigen-1mentioning

confidence: 96%

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

2019

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Current pain therapeutics offer inadequate relief to patients with chronic pain. A growing literature supports that pro-inflammatory cytokine signaling between immune, glial, and neural cells is integral to the development of pathological pain. Modulation of these communications may hold the key to improved pain management. In this review we first offer an overview of the relationships between pro-inflammatory cytokine and chemokine signaling and pathological pain, with a focus on the actions of cytokines and chemokines in communication between glia (astrocytes and microglia), immune cells (macrophages and T cells), and neurons. These interactions will be discussed in relation to both peripheral and central nervous system locations. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways. Preclinical investigation of the mechanisms underlying the success of IL-10 gene therapy revealed the unexpected discovery of the powerful anti-nociceptive anti-inflammatory properties of D-mannose, an adjuvant in the non-viral gene therapeutic formulation. This review will include gene therapeutic approaches showing the most promise in controlling pro-inflammatory signaling via increased expression of anti-inflammatory cytokines like interleukin-10 (IL-10) or IL-4, or by directly limiting the bioavailability of specific pro-inflammatory cytokines, as with tumor necrosis factor (TNF) by the TNF soluble receptor (TNFSR). Approaches that increase endogenous anti-inflammatory signaling may offer additional opportunities for pain therapeutic development in patients not candidates for gene therapy. Promising novel avenues discussed here include the disruption of lymphocyte function-associated antigen (LFA-1) activity, antagonism at the cannabinoid 2 receptor (CB2R), and toll-like receptor 4 (TLR4) antagonism. Given the partial efficacy of current drugs, new strategies to manipulate neuroimmune and cytokine interactions hold considerable promise.

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Section: Lymphocyte Function-associated Antigen-1mentioning

confidence: 96%

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

2019

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“…It is an inducible transmembrane surface glycoprotein that mediates adhesion-dependent cell-to-cell interactions. Endothelial cell surface ICAM-1 contributes to the adhesion and transmigration of leucocytes that express its ligand molecule LFA-1 (leucocyte function-associated antigen-1), such as neutrophils, monocytes, lymphocytes and natural killer cells (Springer 1990, Schenkel et al 2004, Verma & Kelleher 2017, Walling & Kim 2018. In addition to mediating cell migration, ICAM-1 is involved in osteoclastogenesis by mediating adhesion between osteoblasts and osteoclast precursors via an interaction with LFA-1 located on osteoclast precursors (Kurachi et al 1993, Harada et al 1998, Bloemen et al 2010.…”

mentioning

confidence: 99%

Effect of intercellular adhesion molecule 1 deficiency on the development of apical periodontitis

Rossi¹,

Lucisano²,

Rossi³

et al. 2019

Int Endodontic J

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Aim To evaluate the specific role of ICAM‐1 in host responses against endodontic infection. Methods Apical periodontitis was experimentally induced in the mandibular first molars of ICAM‐1 knockout and wild‐type (WT) mice by pulp exposure to the oral environment. At 7, 21 and 42 days following pulp infection, the animals were euthanized and the jaws were prepared for analysis under conventional and fluorescence microscopy (histopathologic and morphometric analysis), immunohistochemistry (polymorphonuclear leucocytes), enzyme histochemistry (osteoclasts and cementoclasts) and RT‐PCR (IL‐1 α, TNF‐α, INF‐γ, IL‐10, RANK, RANKL and OPG). A generalized linear model with GLIMMIX procedure with Satterthwaite approximation method of degrees of freedom, Tukey–Kramer, pseudo‐ranking nonparametric, Bonferroni–Holm multiple testing adjustment, analysis of variance (ANOVA) and the Tukey's multiple comparisons tests were used to evaluate the statistical differences between the groups using SAS 9.4 and the GraphPad Prism 5.0 software (α = 0.05). Results Compared to WT mice, ICAM‐1 knockout mice had significantly greater bone resorption (P < 0.05), reduced recruitment of neutrophils to periapical inflammatory tissues (P < 0.05) and an increased number of fibroblasts (P < 0.05) at all experimental periods. The osteoclast number was significantly higher in ICAM‐1 KO than that of WT animals at all times (P < 0.05), while there was no significant difference between the groups regarding cementoclasts. At day 21, the level of IL‐1α, RANK, RANKL and IL‐10 had increased significantly in tissues from ICAM‐1 KO versus WT mice (P < 0.05), while no significant difference was observed in TNF‐α and OPG levels (P > 0.05). Tissue levels of INF‐γ were significantly lower in ICAM‐1 KO than those in WT mice (P < 0.05). Conclusion ICAM‐1 deficiency impaired the host response against endodontic infection, resulting in increased tissue destruction.

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“…The function of leukocyte integrins, especially LFA‐1, and their role in signaling and cell migration have been extensively reviewed elsewhere (Hogg, Patzak, & Willenbrock, 2011; Verma & Kelleher, 2017; Walling & Kim, 2018). Briefly, LFA‐1 is a transmembrane glycoprotein that functions as an adhesion and signaling receptor on the surface of leukocytes, which upon activation, binds with the ligand intercellular adhesion molecule 1 (ICAM1) preceding transmigration of the cell into tissue.…”

Section: Host Cell Interactionsmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Krueger

Brown

2020

Molecular Oral Microbiology

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Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium associated with localized aggressive periodontitis, as well as other systemic diseases. This organism produces a number of virulence factors, all of which provide some advantage to the bacterium. Several studies have demonstrated that clinical isolates from diseased patients, particularly those of African descent, frequently belong to specific clones of A. actinomycetemcomitans that produce significantly higher amounts of a protein exotoxin belonging to the repeats-in-toxin (RTX) family, leukotoxin (LtxA), whereas isolates from healthy patients harbor minimally leukotoxic strains. This finding suggests that LtxA might play a key role in A. actinomycetemcomitans pathogenicity. Because of this correlation, much work over the past 30 years has been focused on understanding the mechanisms by which LtxA interacts with and kills host cells.In this article, we review those findings, highlight the remaining open questions, and demonstrate how knowledge of these mechanisms, particularly the toxin's interactions with lymphocyte function-associated antigen-1 (LFA-1) and cholesterol, enables the design of targeted anti-LtxA strategies to prevent/treat disease. K E Y W O R D SAggregatibacter actinomycetemcomitans, leukotoxin, LFA-1, repeats-in-toxin

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Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program

Cited by 86 publications

References 111 publications

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

Effect of intercellular adhesion molecule 1 deficiency on the development of apical periodontitis

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

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