Targeting Rho‐GTPases in immune cell migration and inflammation

Abstract

Leukocytes are unmatched migrators capable of traversing barriers and tissues of remarkably varied structural composition. An effective immune response relies on the ability of its constituent cells to infiltrate target sites. Yet, unwarranted mobilization of immune cells can lead to inflammatory diseases and tissue damage ranging in severity from mild to life-threatening. The efficacy and plasticity of leukocyte migration is driven by the precise spatiotemporal regulation of the actin cytoskeleton. The small GTPases of the Rho family (Rho-GTPases), and their immediate downstream effector kinases, are key regulators of cellular actomyosin dynamics and are therefore considered prime pharmacological targets for stemming leukocyte motility in inflammatory disorders. This review describes advances in the development of small-molecule inhibitors aimed at modulating the Rho-GTPase-centric regulatory pathways governing motility, many of which stem from studies of cancer invasiveness. These inhibitors promise the advent of novel treatment options with high selectivity and potency against immune-mediated pathologies.Linked ArticlesThis article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24

Fluid-flow-induced mesenchymal stem cell migration: role of focal adhesion kinase and RhoA kinase sensors

“…The Rac and Rho pathways are generally antagonistic with complex spatio-temporal regulation, which is poorly understood to date [32]. Because it was shown for leucocytes under static culture that Rac plays a role associated with cytoskeletal protrusions at the leading edge of the cell migration [30], evaluating the role of Rac in MSC migration under physiologically relevant shear stress will greatly broaden our understanding of the underlying molecular mechanisms in MSC migration and homing.…”

Direct Modulation of Small GTPase Activity and Function

“…Form ore detailed discussions,t he interested reader should consult additional in-depth reviews about individual Ras subfamilies, [12-18, 20, 22, 27, 40, 41] their GEF,G AP,a nd GDI regulation, [6,7,10,42] and their involvement in various diseases. [21,25,29,[43][44][45] This Review will first discuss the potential of compounds that interfere with nucleotide binding,followed by covalent inhibitors that form irreversible adducts with small GTPases (Figure 2). Subsequently,w ep resent inhibitors of small GTPase-GEF interactions and GTPase-effector interactions.L astly,w ed escribe stabilizers of these PPIs, and conclude by discussing recent advances and offer ideas for future approaches and strategies.…”

Immunomodulatory Yersinia outer proteins (Yops)–useful tools for bacteria and humans alike

“…82,83 By hitting Rho-GTPases, YopE not only attenuates the production of IL-8 (CXCL8), an important chemoattractant and activator for neutrophils, 84 but should also severely affect neutrophil migration, which is largely dependent on Rho-mediated signaling. 85 An increasing number of research projects is directed toward an inhibition of neutrophil migration and/or activity as well as modulation of Rho-GTPases for the treatment of IBD or autoinflammatory disorders in general. [85][86][87][88][89] In line with this, YopE -together with YopT -has been proposed as an inhibitor of caspase-1 activation, since chemical inhibitors of Rho-GTPases also had a negative effect on caspase-1.…”

“…85 An increasing number of research projects is directed toward an inhibition of neutrophil migration and/or activity as well as modulation of Rho-GTPases for the treatment of IBD or autoinflammatory disorders in general. [85][86][87][88][89] In line with this, YopE -together with YopT -has been proposed as an inhibitor of caspase-1 activation, since chemical inhibitors of Rho-GTPases also had a negative effect on caspase-1. Indeed, transfected YopE or YopT was able to block IL-1b secretion by HEK293T cells through inhibition of the Rac1-LIMK-1-pathway, leading to impaired activation of caspase-1.…”