Triggering the Resolution of Immune Mediated Inflammatory Diseases: Can Targeting Leukocyte Migration Be the Answer?

Hopkin, Sophie J.; Lewis, Jonathan W.; Krautter, Franziska; Chimen, Myriam; McGettrick, Helen M.

doi:10.3389/fphar.2019.00184

Cited by 15 publications

(18 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chemokines modulate the movement of different cell types and populations into and out of the sites of affection in all chronic inflammatory conditions. Because these cells are in large part responsible for the pathological manifestations of these diseases, the clinical regulation of their movement is a long sought-after but as yet unrealized therapeutic target for their treatment [20]. Chemokines are a large group of related cytokines mediating cell movement that act by interacting with their cognate chemokine receptors [28].…”

Section: Discussionmentioning

confidence: 99%

“…In inflammation-driven disease, chemokines play a central role by mediating cell migration and have, therefore, long been considered a critical target for the development of new therapies [20]. Guided by our previously described observations of the poxviral model, we hypothesized that addition of a viral chemokine inhibitor such as the SECRET domain to currently in use inhibitors of TNF could generate more effective biologicals for the treatment of inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

Alejo

Sánchez

Amu

et al. 2019

JCM

View full text Add to dashboard Cite

The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein.A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

Alejo

Sánchez

Amu

et al. 2019

JCM

View full text Add to dashboard Cite

show abstract

“…Nevertheless, our study provides an update that ursolic acid inhibited leukocytes migration by reducing the level of chemokines (IL-8 and MCP-1). Since targeting leukocyte migration induced by chemokines is a promising approach to resolve inflammation (Hopkin et al, 2019), ursolic acid might represent a potential compound to be developed as an anti-inflammatory agent. Although ursolic acid has been reported to exert anti-inflammatory activity by inhibition of proinflammatory transcription factor such as NF-ĸB, Volume 30 Issue 4 (2019) NF-AT, and AP-1, this result reveals an additional anti-inflammatory mechanism of action of ursolic acid (Checker et al, 2012).…”

Section: Percentage Of Leukocyte Migrationmentioning

confidence: 99%

“…The roles of chemokines in leukocyte migration in inflammation have been established in many studies (Charo and Taubman, 2004;Turner et al, 2014). Thus, inhibiting leukocyte migration by reducing chemokine levels is a promising therapeutic target in inflammatory-related diseases (Del Prete et al, 2015;Hopkin et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The Effect of Ursolic Acid from Plantago Lanceolata Leaves on Leukocytes Migration and Chemokines Level

Fakhrudin

Franyoto

Astuti

et al. 2019

Indonesian J. Pharm.

View full text Add to dashboard Cite

Initially considered as a normal body response to injury, inflammation is currently known as a major event contributing to the development of many human disorders. Many drugs and bioactive molecules have been discovered from medicinal plants and the number is still growing by time. Among those medicinal plants used in folk medicines, Plantago lanceolata is used to cure inflammatory-related diseases. In our previous study, we showed that the n-hexane insoluble fraction of P. lanceolata leaves (HIF) demonstrated a potent anti-inflammatory activity by inhibiting leukocytes migration in mice. This study aimed to identify the active compound from HIF which responsible for the inhibition of leukocytes migration in mice, and to investigate the effect of the active compound on the level of chemokine (IL-8 and MCP-1) responsible for leukocytes migration. P. lanceolata leaves were initially macerated with dichloromethane. The dried extract was partitioned using n-hexane to obtain n-hexane soluble fraction (HSF) and n-hexane insoluble fraction (HIF). Both fractions were evaluated for their anti-inflammatory activity in thioglycollate-induced leukocyte migration. The active fraction (HIF) was subjected to a preparative thin-layer chromatography to isolate the major compound. The structure of the isolated compound was identified based on NMR, IR, and Mass spectra. The compound was identified as ursolic acid, based on its spectral data. Ursolic acid at dose of 30, 60, and 120mg/kg BW inhibited leukocyte migration and reduced the level of IL-8 and MCP-1).

show abstract

“…Leukocytes, including macrophages and neutrophils, possess a sophisticated chemosensory system that controls cellular migration up primary attractant gradients to sites of infection, injury, or tumor formation during the innate immune response [1][2][3][4][5][6][7][8]. At the target site, recruited leukocytes and other cells can release secondary attractants that recruit additional leukocytes, but excessive secondary attractant signaling and recruitment may lead to local inflammation and, in extreme cases, toxic effects (reviewed in [9][10][11][12][13][14]).…”

Section: Introductionmentioning

confidence: 99%

Rapid exposure of macrophages to drugs resolves four classes of effects on the leading edge sensory pseudopod: Non-perturbing, adaptive, disruptive, and activating

et al. 2020

View full text Add to dashboard Cite

Leukocyte migration is controlled by a membrane-based chemosensory pathway on the leading edge pseudopod that guides cell movement up attractant gradients during the innate immune and inflammatory responses. This study employed single cell and population imaging to investigate drug-induced perturbations of leading edge pseudopod morphology in cultured, polarized RAW macrophages. The drugs tested included representative therapeutics (acetylsalicylic acid, diclofenac, ibuprofen, acetaminophen) as well as control drugs (PDGF, Gö 6976, wortmannin). Notably, slow addition of any of the four therapeutics to cultured macrophages, mimicking the slowly increasing plasma concentration reported for standard oral dosage in patients, yielded no detectable change in pseudopod morphology. This finding is consistent with the well established clinical safety of these drugs. However, rapid drug addition to cultured macrophages revealed four distinct classes of effects on the leading edge pseudopod: (i) non-perturbing drug exposures yielded no detectable change in pseudopod morphology (acetylsalicylic acid, diclofenac); (ii) adaptive exposures yielded temporary collapse of the extended pseudopod and its signature PI(3,4,5)P 3 lipid signal followed by slow recovery of extended pseudopod morphology (ibuprofen, acetaminophen); (iii) disruptive exposures yielded long-term pseudopod collapse (Gö 6976, wortmannin); and (iv) activating exposures yielded pseudopod expansion (PDGF). The novel observation of adaptive exposures leads us to hypothesize that rapid addition of an adaptive drug overwhelms an intrinsic or extrinsic adaptation system yielding temporary collapse followed by adaptive recovery, while slow addition enables gradual adaptation to counteract the drug perturbation in real time. Overall, the results illustrate an approach that may help identify therapeutic drugs that temporarily inhibit the leading edge pseudopod during extreme inflammation events, and toxic drugs that yield long term inhibition of the pseudopod with negative consequences for innate immunity. Future studies are needed to elucidate the mechanisms of drug-induced pseudopod collapse, as well as the mechanisms of adaptation and recovery following some inhibitory drug exposures.

show abstract

Triggering the Resolution of Immune Mediated Inflammatory Diseases: Can Targeting Leukocyte Migration Be the Answer?

Cited by 15 publications

References 117 publications

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

The Effect of Ursolic Acid from Plantago Lanceolata Leaves on Leukocytes Migration and Chemokines Level

Rapid exposure of macrophages to drugs resolves four classes of effects on the leading edge sensory pseudopod: Non-perturbing, adaptive, disruptive, and activating

Contact Info

Product

Resources

About