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Biology of Disease 0023-6837/00/8005-617$03.00/0 LABORATORY INVESTIGATION Vol. 80, No. 5, p. 617, 2000 Copyright © 2000 by The United States and Canadian Academy of Pathology, Inc. Printed in U.S.A. BIOLOGY OF DISEASE Neutrophils: Molecules, Functions and Pathophysiological Aspects Ve´ ronique Witko-Sarsat, Philippe Rieu, Be´ atrice Descamps-Latscha, Philippe Lesavre, and Lise Halbwachs-Mecarelli INSERM U507, Necker Hospital, Paris, France INTRODUCTION I. NEUTROPHIL MOLECULES AND FUNCTIONS IL-10 I.A. ADHESION AND MIGRATION IL-4 and IL-13 I.A.1. Traffic and margination I.C.5. Molecular Regulation of Cytokine Produc- I.A.2. Adhesion to the Endothelial Wall tion Rolling and Tethering I.D. APOPTOSIS AND RESOLUTION OF ACUTE Neutrophil Priming During Rolling INFLAMMATION Firm Adhesion and Spreading I.D.1. Progressive Decrease of Neutrophil Recruit- I.A.3 Extravasation and Diapedesis Toward In- ment flammatory Stimuli I.D.2. Apoptosis in Resolution of Inflammation Transendothelial Migration II. NEUTROPHILS IN PATHOLOGY Migration Within Interstitial Tissues II.A. Bacterial Infection Signaling by Chemoattractants II.B. Tissue Injury-Induced Inflammation: Ischemia- Transepithelial Migration Reperfusion Injury I.B. PHAGOCYTOSIS, DEGRANULATION AND II.C. Crystal-Induced Inflammation BACTERIA KILLING II.D. Complement-Induced Inflammation and Ox- I.B.1. Phagocytosis idative Stress: Hemodialysis I.B.2. Degranulation II.E. Immune Complex-Induced Inflammation: Granule Biogenesis Antibody-Mediated Glomerunephritis Mechanisms of Degranulation II.F. Cytokine-Induced Inflammation: Rheumatoid I.B.3. Microbicidal Molecules Arthritis NADPH-Derived Oxidants II.G. Antineutrophil Cytoplasmic Antibodies and The H2O2-Myeloperoxidase System Vasculitis: Autoimmunity Against Neutrophil Nitric Oxide-Synthase-Derived Reactive Nitro- Components gen Intermediates II.H. Genetic Disorders of Neutrophil Regulations: Granule Proteins Hereditary Periodic Fever Syndromes Antimicrobial Proteins II.I. Cystic Fibrosis: The Paradox of an Exacerba- Proteases tion of Neutrophil-Mediated Tissue Damage I.C. CYTOKINE SYNTHESIS and a Concomitant Persistence of Infection I.C.1. TNF-␣ as a Proinflammatory Cytokine CONCLUSION I.C.2. IL-1 and IL-1 Receptor Antagonist (IL-1-Ra) I.C.3. IL-8 as a Prototype of Chemokines he notion that inflammation is the net resultant of I.C.4. Modulation of Cytokine Expression by Neu- T pro and contra inflammatory pathways (Fauve, trophils 1980) is well illustrated by the dual role of neutrophils IFN-␥ which combine an anti-infectious and a proinflamma- tory role (Klebanoff, 1992; Ward, 1999; Weiss, 1989). The aim of this report is to review the main physiolog- Received February 8, 2000. ical and pathogenic activities of neutrophils—ie, ad- Address reprint requests to: Dr. V. Witko-Sarsat, INSERM U507, Necker herence and migration, degranulation and release of Hospital, 161, rue de Se`vres, 75015 Paris, France. Fax: 01 45 66 51 33; inflammatory mediators, phagocytosis and apopto- E-mail: witko-sarsat @necker.fr sis—in the light of the most recent molecular data on Laboratory Investigation • May 2000 • Volume 80 • Number 5 617 Witko-Sarsat et al extracellular effectors and regulators, membrane re- pool” (Peters, 1998), comprises granulocytes tran- ceptors, and intracellular signaling pathways involved siently arrested in narrow, mainly pulmonary, capillar- in these functions. ies. This physiological retention of neutrophils in cap- Leukocyte adhesion processes have been studied illaries appears to be a mechanical process due to the extensively during the last decade and most mem- stiffness of neutrophils—as compared with the high brane molecules responsible for leukocyte interac- deformability of erythrocytes (Downey et al, 1990)— tions with other cells or with the extracellular matrix and does not involve cell adhesion (Doyle et al, 1997; have been identified. New data are constantly re- Mizgerd et al, 1996; Yamaguchi et al, 1997; Yoder et ported on sophisticated intracellular pathways that al, 1990). allow neutrophils to integrate signals transmitted by Conversely, in inflamed organs, neutrophil traffic adhesion partners with those of chemoattractants and involves a selectin- and integrin-dependent seques- cytokines. What remains puzzling is that leukocytes tration in capillaries and post-capillary venules (Adams mostly use the same adhesion molecules to adhere to and Shaw, 1994; Springer, 1994). Intravascular injec- inflamed endothelium, as do lymphocytes to con- tion of inflammatory mediators first results in rapid stantly recirculate from the blood to lymphoid tissues. sequestration that involves a decrease in neutrophil Still, naive lymphocytes are the only leukocytes to deformability, followed by prolonged accumulation of cross endothelia of lymphoid high endothelial venules, neutrophils in the lung and liver parenchyma, by a while neutrophils are the first leukocytes, hours before process involving CD11b/CD18 integrins and monocytes or lymphocytes, to migrate specifically L-selectin (Doerschuk, 1992; Doyle et al, 1997; Er- across the endothelium adjacent to the inflammation zurum et al, 1992; Hogg and Doerschuk, 1995; Jae- site. The selectivity and specific timing of such a highly schke and Smith, 1997; Tedder et al, 1995). Mecha- redundant system is just becoming comprehensible, nisms involving adhesion also occur when neutrophil in particular with the description of the chemokine and emigration follows instillation of stimuli in airways, serpentine families. peritoneum, or skin. Defective neutrophil recruitment Another aspect reviewed here is the wide variety of to inflamed sites in leukocyte adhesion deficient (LAD) effector molecules required to achieve the usual mi- patients and in adhesion molecules-knock-out mice crobicidal role of neutrophils, including radical oxygen shows that these emigration processes require selec- species (ROS), proteinases, bactericidal proteins and tins (Borges et al, 1997; Bullard et al, 1996; Doyle et al, cytokines, which either alone or in concert may inter- 1997; McEver and Cummings, 1997; Tedder et al, act in up- or down-regulating the major inflammatory 1995) and the interactions of leucocyte CD18 integrins processes. We emphasize new directions of investi- with endothelial ICAM-1 (Mizgerd et al, 1997; Sligh et gation regarding these neutrophil-derived effector al, 1993). However, animal models using intratracheal molecules, as exemplified by myeloperoxidase- instillation of Streptococcus pneumonia suggest that derived oxidants whose implications go far beyond neutrophil pulmonary traffic, at least in mice and inflammatory diseases. The potential clinical use of rabbits, may differ from what happens in the systemic neutrophil-derived antibiotic proteins is illustrated by circulation and in some cases may involve selectin- the Bactericidal Permeability Increasing protein (BPI), and integrin-independent emigration from systemic now undergoing clinical trials, and the design of novel venules (Mizgerd et al, 1996). antimicrobial peptides based on studies on defensins and cathelicidins. Finally, we illustrate the various aspects of neutro- I.A.2. Adhesion to the Endothelial Wall phil biology by classifying, according to their predom- inant neutrophil-activating mechanism, diseases in The dual neutrophil functions of immune surveillance which neutrophils play a pivotal role. Comprehension and in situ elimination of microorganisms or cellular of the activation pathways will allow us to analyze, and debris require a rapid transition between a circulating possibly prevent, chronic inflammation processes non-adherent state to an adherent state, allowing where dysregulated neutrophil recruitment and activa- them to migrate into tissues where necessary. The tion results in severe damage of adjacent normal initial event is the appearance, on the endothelium tissues. adjacent to the inflamed site, of new adhesion mole- cules, induced by inflammation mediators released by damaged tissues, which result in local extravasation of I. Neutrophil Molecules and Functions leukocytes. In postcapillary venules or in pulmonary capillaries, the slow flow rate, further reduced by I.A. Adhesion and Migration vessel dilatation at sites of inflammation, allows a I.A.1. Traffic and Margination loose and somewhat transient adhesion, referred to as “tethering,” and resulting in the rolling of leukocytes Neutrophils are partitioned in the blood between a along the endothelium. During this tethering step, circulating pool, present in large blood vessels and in neutrophils respond to ligands—mainly chemokines— the axial stream of small vessels, and a marginating dispatched on the endothelium surface by a signaling pool. In the absence of inflammation, the marginating event that activates integrin-mediated sustained, sta- pool, better called “physiological regional granulocyte tionary adhesion and spreading (Springer, 1994). 618 Laboratory Investigation • May 2000 • Volume 80 • Number 5 Neutrophils Rolling and Tethering endothelial cells not only synthesize IL-8 in response to IL-1 or LPS, but also store IL-8 in Weibel-Palade The rolling step is mediated by neutrophil L-selectin bodies and release it upon stimulation by histamine or and by E- and P-selectins newly expressed on in- thrombin (Utgaard et al, 1998; Wolff et al, 1998). flamed endothelial cells. Rare deficits in neutrophil Moreover, tissue-derived IL-8 is internalized by endo- selectin ligand expression, due to a metabolic defect thelial cells of postcapillary venules and small veins, in a synthetic
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