Endothelium-Neutrophil Interactions in ANCA-Associated Diseases

BRIEF REVIEW www.jasn.org Endothelium-Neutrophil Interactions in ANCA-Associated Diseases † Lise Halbwachs* and Philippe Lesavre* *Institut National de la Santé et de la Recherche Medicale INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, France; and †Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France ABSTRACT The two salient features of ANCA-associated vasculitis (AAV) are the restricted without activation that could result from microvessel localization and the mechanism of inflammatory damage, independent neutrophil-neutrophil interactions, of vascular immune deposits. The microvessel localization of the disease is due to contact with endothelium, or distortion; the ANCA antigen accessibility, which is restricted to the membrane of neutrophils and neutrophil adhesion to inflamed en- engaged in b2-integrin–mediated adhesion, while these antigens are cytoplasmic dothelium and diapedesis through the and inaccessible in resting neutrophils. The inflammatory vascular damage is the vessel wall should occur without release consequence of maximal proinflammatory responses of neutrophils, which face cu- of toxic oxidants or proteases, which mulative stimulations by TNF-a, b2-integrin engagement, C5a, and ANCA by the should be delayed until cells reach the FcgRII receptor. This results in the premature intravascular explosive release by inflammatory focus. This review exam- adherent neutrophils of all of their available weapons, normally designed to kill ines current concepts of the ways ANCA IgG-opsonized bacteria after migration in infected tissues. disrupts these sophisticated regulatory mechanisms, leading to unwanted pre- J Am Soc Nephrol 23: 1449–1461, 2012. doi: 10.1681/ASN.2012020119 mature and improperly located neutrophil activation, almost exclusively in microvessels. The initial description of small-vessel with the endothelium in ANCA-associated – vasculitides dates back to 1950, when vasculitis (AAV).6 8 NEUTROPHILS IN THE BLOOD Wainwright and Davson, by ocular ex- Endothelium-neutrophil interactions FLOW: PHYSIOLOGIC CONTROL amination of kidneys conserved in the are essential to allow neutrophils to move AND ACTIVATION BY ANCA Pathologic Museum of Manchester, were toward inflammatory sites and regulate able to distinguish forms of vasculitis spatially and temporally neutrophil re- Physiologic Control of TNF-Primed fl with enlarged and in ammatory glomer- cruitment. Neutrophils contain intracel- Neutrophils uli involving mostly vessels smaller than lular pools of toxic proteins aimed to kill The central role of TNF-a in AAV is 1 fi — arteries. Their de nition of a micro- microbes and digest tissues. To perform demonstrated in vitro9,10 and in vivo by — scopic form of periarteritis nodosa innate immune responses to infections, the striking effect of anti-TNF anti- fi was speci ed in 1994 by an international neutrophils must adhere and migrate bodies in experimental anti-MPO– 2 consensus committee, who changed the toward the site of infection (Figure 1), induced GN11,12 and in human AAV.13–15 name to microscopic polyangiitis be- while avoiding collateral damage caused Circulating TNF-a results in neutro- fl cause of the localization of in ammatory by premature release of oxidants and phil priming, leading to weak degranu- lesions in arterioles, venules, but not in proteolytic enzymes. This implies highly lation, oxidative response, or adhesion medium-sized or small arteries.3 The regulated neutrophil-endothelial cell in- original observation that small-vessel teractions complying with the following vasculitis, including granulomatous demands: neutrophils must remain Published online ahead of print. Publication date polyangiitis (GPA) and microscopic nonadhesive in the arterial and arteriolar available at www.jasn.org. polyangiitis, was associated with anti- circulation, independently of their re- Correspondence: Dr. Philippe Lesavre, Néphrol- 4 proteinase 3(PR3) or antimyeloperoxidase cruitment in postcapillary venules of ogie Adultes, Hôpital Necker, 149 rue de Sèvres, (MPO)5 ANCA, produced numerous inflammatory organs; the 10-mmdiam- 75015 Paris. Email: [email protected] studies that demonstrated the central eter neutrophil must squeeze through Copyright © 2012 by the American Society of role of neutrophils and their interaction capillaries, smaller in diameter (7 mm), Nephrology J Am Soc Nephrol 23: 1449–1461, 2012 ISSN : 1046-6673/2309-1449 1449 BRIEF REVIEW www.jasn.org homotypic aggregation,22 which is favored by the presence of cell-bound C3 fragments interacting with CR1 and CR3 (Mac-1) receptors, for C3b and iC3b, re- spectively, on bystander neutrophils. Moreover, TNF priming triggers the switching of the aMb2-integrin (Mac-1) to an active conformation, allowing its binding to intracellular adhesion molecule 3 (ICAM-3) on adjacent neutrophils.23 It is thus reasonable to propose an initial step of low-grade activation of circulating neutrophils (Figure 2B) promoted by TNF-a and complement, Figure 1. Neutrophil-endothelial cell interactions. The classic view of neutrophil inter- allowing neutrophil-neutrophil interac- actions with activated endothelium is a three-step process, although the development of tions through b2-integrin binding of intravital imaging recently revealed intermediate steps, such as the slow rolling and the iC3b and/or ICAM-3. This would re- intravascular crawling. Step 1 entails tethering and rolling involving selectins. Proin- sult in a transient homotypic aggrega- flammatory cytokines (TNF-a, IL1-b) or LPS induce the expression of endothelial selectins, tion, similar to that observed in the able to interact with different ligands (PSGL-1, ESL-1, CD44) on neutrophils. Selectin en- Shwartzmann phenomenon24 and to gagement mediates rolling and, together with chemokines induced on the endothelial that recently described after in vivo injec- surface, initiates the “inside-out” activation of neutrophil b2-integrins. The interaction of tion of granulocyte-colony stimulating partly activated b2-integrins leads first to neutrophils slow rolling on endothelial ICAM-1 25 and E-selectin. During this slow rolling, leukocytes integrate signals from chemokines or factor. These neutrophil-neutrophil in- lipid mediators important for downstream events. Step 2 entails firm attachment via interactions might be stabilized by ANCA, tegrins. The level of intracellular calcium rises, leading to full b2-integrin activation and firm as the b2-integrin–induced firm adhe- arrest on ICAMs. Chemokines trigger the polarization of leukocytes, with the formation of sion.26 This implies that b2-integrin– leading and trailing edges. The activation of aMb2 (Mac-1) at the leading edge promotes mediated homotypic interactions would intravascular crawling on the luminal surface to the point of transmigration. Intravital im- promote low ANCA antigen expression aging allows for distinguishing two ways of transendothelial migration. As shown in step 3, on circulating neutrophils, accessible the paracellular migration through endothelial junctions involves homotypic PECAM-1 and to ANCA autoantibodies in serum, as junctional adhesion molecule-A (JAM) interactions, resulting in unzipping of the endo- has been observed during b2-integrin– thelial cell junctions. In the transcellular migration, high density of ICAM-1 and VCAM-1 on mediated adhesion.27 This would allow specialized docking structures (migratory cup) captures crawling neutrophils and facilitates ANCA to bind neutrophils and trigger a their way through the endothelial cells.123,124 massive activation otherwise normally expected at infected sites in tissues. and to hyperresponsiveness to subsequent Early Misleading Signals and stimuli such as chemoattractants or im- Homotypic Aggregation munecomplexes.16,17 TNF-inducedprim- In AAV, excessive amounts of fluid phase NEUTROPHIL ADHESION AND ing has normally limited consequences inflammatory stimuli in plasma may ANCA-INDUCED ACTIVATION within the blood flow of circulation due provide misguided information to neu- to a strict control of neutrophil activation trophils, suggesting an intravascular in- Neutrophil Adhesion in Capillaries by the plasma itself (Figure 2A). fection and leading to premature cell and Postcapillary Venules Under physiologic conditions, flow- activation. Levels of circulating TNF-a Contacts with the vascular wall along ing neutrophils do not interact with the and IL-8 are indeed increased in ANCA capillaries would be favored by the de- resting endothelium. They adhere only vasculitis.18,19 High concentrations of creased deformability of neutrophils in response to the local expression of ad- Fc-reactive ANCA could provide these treated with TNF-a and C5a, particu- hesion molecules, chemokines, and bio- misleading signals as suggested by the larly in the presence of ANCA28 and by active lipids on the endothelial surface glomerular neutrophil adhesion ob- neutrophil homotypic interactions. Cir- due to tissue inflammation and release served in naïve LPS mice upon the in- culating IL-8 also inhibits the emigration of cytokines along the basal side of jection of high doses of anti-MPO of neutrophils and promotes their se- endothelium. The recruitment of neu- antibodies.20 C5a may also play an im- questration in the microvasculature trophils is thus restricted locally and portant role because neutrophils activate due to downregulation of neutrophil cell activation is delayed until they complement and release C5a when stim- CXCR1/CXCR2 receptors internalized have migrated and reached

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