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      Organ-Specific Mechanisms of Transendothelial Neutrophil Migration in the Lung, Liver, Kidney, and Aorta

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          Abstract

          Immune responses are dependent on the recruitment of leukocytes to the site of inflammation. The classical leukocyte recruitment cascade, consisting of capture, rolling, arrest, adhesion, crawling, and transendothelial migration, is thoroughly studied but mostly in model systems, such as the cremasteric microcirculation. This cascade paradigm, which is widely accepted, might be applicable to many tissues, however recruitment mechanisms might substantially vary in different organs. Over the last decade, several studies shed light on organ-specific mechanisms of leukocyte recruitment. An improved awareness of this matter opens new therapeutic windows and allows targeting inflammation in a tissue-specific manner. The aim of this review is to summarize the current understanding of the leukocyte recruitment in general and how this varies in different organs. In particular we focus on neutrophils, as these are the first circulating leukocytes to reach the site of inflammation. Specifically, the recruitment mechanism in large arteries, as well as vessels in the lungs, liver, and kidney will be addressed.

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          Most cited references204

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          Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.

          It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.
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            Anti-inflammatory therapy in chronic disease: challenges and opportunities.

            A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer's disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.
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              How leukocytes cross the vascular endothelium.

              Immune responses depend on the ability of leukocytes to move from the circulation into tissue. This is enabled by mechanisms that guide leukocytes to the right exit sites and allow them to cross the barrier of the blood vessel wall. This process is regulated by a concerted action between endothelial cells and leukocytes, whereby endothelial cells activate leukocytes and direct them to extravasation sites, and leukocytes in turn instruct endothelial cells to open a path for transmigration. This Review focuses on recently described mechanisms that control and open exit routes for leukocytes through the endothelial barrier.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                27 November 2018
                2018
                : 9
                : 2739
                Affiliations
                [1] 1Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München , Munich, Germany
                [2] 2German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance , Munich, Germany
                [3] 3Department of Physiology and Pharmacology (FyFa) and Department of Medicine, Karolinska Institutet , Stockholm, Sweden
                Author notes

                Edited by: Susanna Carola Fagerholm, University of Helsinki, Finland

                Reviewed by: María J. Sanz, University of Valencia, Spain; Christian David Sadik, Universität zu Lübeck, Germany

                *Correspondence: Sanne L. Maas sanne.maas@ 123456med.uni-muenchen.de

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.02739
                6277681
                30538702
                c6188b2c-8bc2-44bd-995e-9bd975341857
                Copyright © 2018 Maas, Soehnlein and Viola.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 03 September 2018
                : 07 November 2018
                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 267, Pages: 24, Words: 20069
                Categories
                Immunology
                Review

                Immunology
                neutrophil,recruitment,lung,liver,kidney,aorta,inflammation,organ-specific
                Immunology
                neutrophil, recruitment, lung, liver, kidney, aorta, inflammation, organ-specific

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