A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase

Current Opinion in Hematology

et al. 2016

Self Cite

Purpose of review Neutrophils have traditionally been viewed in the context of acute infection and inflammation forming the first line of defence against invading pathogens. Neutrophil trafficking to the site of inflammation requires adhesion and transmigration through blood vessels, which is orchestrated by adhesion molecules, such as β2- and β1-integrins, chemokines and cytokines. This review focuses on recent advances in understanding the regulators of neutrophil recruitment during inflammation in both acute and chronic settings. Recent findings Recent findings suggest that besides the established pathways of selectin or chemokine-mediated integrin activation, signaling by distinct TLRs (especially TLR2, TLR4 and TLR5) can activate integrin-dependent neutrophil adhesion. Moreover, the integrin α3β1 has been vitally implicated as a new player in neutrophil recruitment and TLR-mediated responses in septic inflammation. Furthermore, several endogenous inhibitory mechanisms of leukocyte recruitment have been identified, including the secreted molecules Del-1, PTX3, and GDF-15, which block distinct steps of the leukocyte adhesion cascade, as well as novel regulatory signaling pathways, involving the protein kinase AKT1 and IFN-λ2/IL-28A. Summary The leukocyte adhesion cascade is a tightly regulated process, subjected to both positive and negative regulators. Dysregulation of this process and hence neutrophil recruitment can lead to the development of inflammatory and autoimmune diseases.

Section: Resultsmentioning

confidence: 99%

Section: Novel Regulatory Mechanisms Of Neutrophil Adhesionmentioning

confidence: 99%

Regulation of tissue infiltration by neutrophils

Subramanian

Mitroulis

Current Opinion in Hematology

et al. 2016

Self Cite

Pharmacology & Therapeutics

“…Besides chemokines and PSGL-1-ligation, Toll-like receptors also induce integrin activation (Harokopakis et al, 2006; Harokopakis and Hajishengallis, 2005). Recently, Toll like receptor 2 (TLR2)- and Toll like receptor 5 (TLR5)-ligation was shown to rapidly activate integrin-dependent leukocyte adhesion to immobilized intercellular cell-adhesion molecule 1 (ICAM-1) or fibronectin through activation of a pathway requiring Rac1, NADPH oxidase 2-mediated reactive oxygen species production and activation of Rap1-GTPase (Chung et al, 2014). Furthermore, TLRs activate via Ras the PI3K isoform p100γ, which then promotes activation of the α4β1-integrin (Schmid et al, 2011).…”

Section: The Leukocyte Adhesion Cascadementioning

confidence: 99%

Leukocyte integrins: Role in leukocyte recruitment and as therapeutic targets in inflammatory disease

Mitroulis

Alexaki

Kourtzelis

et al. 2015

Self Cite

232

217

Infection or sterile inflammation triggers site-specific attraction of leukocytes. Leukocyte recruitment is a process comprising several steps orchestrated by adhesion molecules, chemokines, cytokines and endogenous regulatory molecules. Distinct adhesive interactions between endothelial cells and leukocytes and signalling mechanisms contribute to the temporal and spatial fine-tuning of the leukocyte adhesion cascade. Central players in the leukocyte adhesion cascade include the leukocyte adhesion receptors of the β2-integrin family, such as the αLβ2 and αMβ2 integrins, or of the β1-integrin family, such as the α4β1- integrin. Given the central involvement of leukocyte recruitment in different inflammatory and autoimmune diseases, the leukocyte adhesion cascade in general, and leukocyte integrins in particular, represent key therapeutic targets. In this context, the present review focuses on the role of leukocyte integrins in the leukocyte adhesion cascade. Experimental evidence that has implicated leukocyte integrins as targets in animal models of inflammatory disorders, such as experimental autoimmune encephalomyelitis, psoriasis, inflammatory bone loss and inflammatory bowel disease as well as preclinical and clinical therapeutic applications of antibodies that target leukocyte integrins in various inflammatory disorders are presented. Finally, we review recent findings on endogenous inhibitors that modify leukocyte integrin function, which could emerge as promising therapeutic targets.

“…In neutrophils, PTX3 is constitutively stored in specific granules and can be released locally at the neutrophil-endothelial cell interface in response to pro-inflammatory cytokines or triggered by Toll-like receptor agonists [159]. Toll-like receptor activation may therefore not only promote integrin activation and neutrophil recruitment [160], but through the secretion of PTX3 may also initiate a negative feedback loop. In particular, PTX-3 was shown to bind P-selectin on activated endothelial cells, thereby blocking P-selectin interaction with its leukocyte ligand PSGL-1, hence blocking neutrophil rolling on the endothelium under shear stress [133].…”

Section: Endogenous Regulators Of Neutrophil Recruitment To the Pementioning

confidence: 99%

Immune and regulatory functions of neutrophils in inflammatory bone loss

Moutsopoulos

et al. 2016

Seminars in Immunology

Self Cite

113

Although historically viewed as merely anti-microbial effectors in acute infection or injury, neutrophils are now appreciated to be functionally versatile with critical roles also in chronic inflammation. Periodontitis, a chronic inflammatory disease that destroys the tooth-supporting gums and bone, is particularly affected by alterations in neutrophil numbers or function, as revealed by observations in monogenic disorders and relevant mouse models. Besides being a significant debilitating disease and health burden in its own right, periodontitis is thus an attractive model to dissect uncharted neutrophil-associated (patho)physiological pathways. Here, we summarize recent evidence that neutrophils can contribute to inflammatory bone loss not only through the typical bystander injury dogma but intriguingly also through their absence from the affected tissue, where they normally perform important immunomodulatory functions. Moreover, we discuss recent advances in the interactions of neutrophils with the vascular endothelium and – upon extravasation – with bacteria, and how the dysregulation of these interactions leads to inflammatory tissue damage. Overall, neutrophils have both protective and destructive roles in periodontitis, as they are involved in both the maintenance of periodontal tissue homeostasis and the induction of inflammatory bone loss. This highlights the importance of developing approaches that promote or sustain a fine balance between homeostatic immunity and inflammatory pathology.