The lungs possess extraordinary defenses against bacteria and other stimuli. Initial mechanisms of host defense include the very effective mucociliary escalator and the alveolar macrophages,which clearmany stimuli without inducing an inflammatory response and recruitment of circulating leukocytes. When these defenses are overwhelmed, epithelial cells andmacrophages call in help fromoutside the lungs. In response to bacteria, neutrophils are usually first to arrive, and their response is quick, recognizing a need within minutes

Doerschuk, C.M.

Gomez, J.C.

American Journal of Respiratory Cell and Molecular Biology

John C. Gomez

Claire M. Doerschuk

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Activating Integrins Isn’t Always “Beta” for Neutrophil Migration!

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EDITORIALSActivating Integrins Isn’t Always “Beta” for Neutrophil Migration!The lungs possess extraordinary defenses against bacteria and otherstimuli. Initial mechanisms of host defense include the very effectivemucociliary escalator and the alveolarmacrophages, which clear manystimuli without inducing an inflammatory response and recruitmentof circulating leukocytes. When these defenses are overwhelmed,epithelial cells and macrophages call in help from outside the lungs. Inresponse to bacteria, neutrophils are usually first to arrive, and theirresponse is quick, recognizing a need within minutes.Neutrophil adhesion and migration within the pulmonarymicrovasculature are unique in important ways. Neutrophilemigration into the distal lung occurs primarily through thecapillary bed, rather than the postcapillary venules, where theparadigm of leukocyte rolling followed by firm adhesion andmigration was developed (1, 2). The pulmonary capillaries have acomplex geometry of branching segments, and the diameter of atleast half the segments is narrower than a spherical neutrophil sothat rolling cannot occur (3–6). Although the leukocyte adhesioncomplex CD11/CD18 is not always required for neutrophilemigration in the lungs, Pseudomonas aeruginosa inducesCD11/CD18-dependent neutrophil recruitment (6–8).CD18 is the b2-integrin subunit mediating both outside-insignaling after binding of a ligand and inside-out signaling thatresults in activation of the adhesion complex through a two-stepprocess (9–11). Clustering of integrins induced by ligand binding caninitiate association of two cytosolic proteins, talin-1 and kindlin-3, withtwo distinct sites on the short cytoplasmic tail of CD18. Considerabledata suggest that talin-1 initiates the conformational change in allb-integrins from a compact/bent state to an extended closed headpiece(intermediate binding affinity), whereas kindlin-3 is required fortransformation of this intermediate state to an extended openheadpiece state with a high binding affinity for ligands (9, 10).In this issue of the Journal, Wilson and colleagues(pp. 620–627) elegantly ask critical questions about the requirementsfor talin-1 and kindlin-3 in neutrophil migration duringP. aeruginosa–induced pneumonia (12). In striking contrast tostudies showing that these molecules are required for neutrophiltransmigration into the peritoneum (11), talin-1 is not required forneutrophil recruitment into the lungs. Moreover, kindlin-3–nullneutrophils migrate in greater numbers than wild-type neutrophils,suggesting that kindlin-3–null neutrophils have an advantage.Importantly, antibody blockade shows that CD18 is still required foremigration of kindlin-3–null neutrophils.Studies to determine the site within the lungs where neutrophilsenter more abundantly to account for this advantage show that theneutrophils lacking either talin-1 or kindlin-3 have no defect insequestering within the lung capillaries, but do have an advantage inmigrating into the interstitium compared with wild-type neutrophils,suggesting that activated integrins may slow neutrophil transitthrough the interstitium (12). The mutant neutrophils’ advantagedoes not further increase as they migrate from the interstitium intothe lavageable airspace. Walker and colleagues (2, 13, 14) suggestthat the path neutrophils take is through the endothelial junctions onthe thick side of the capillaries, fully accumulating within theinterstitium, and then migrating between type I and type II alveolarepithelial cells into the alveolar space. Taken together, activatedintegrins appear to slow neutrophil migration through theinterstitium, but have less impact on migration through the alveolarepithelium. An alternative explanation, that activated integrinsslow neutrophil migration through the epithelium and result in a“backup” in the interstitium, seems unlikely.These studies are elegantly performed using mice, the bonemarrow of which has been reconstituted with a mixture of mutantand wild-type bone marrow, allowing comparison of each genotypewithin the same mouse. The radiation dose (10 Gy) does inducea lung injury, including replacement of alveolar macrophageswith bone marrow–derived cells and an immune cell infiltratewithin the bronchovascular bundle, but an impact of this on theresults seems unlikely. These studies have the technical caveats thatflushing the vasculature does not completely differentiatebetween the circulating and sequestering neutrophils, and thatbronchoalveolar lavage does not remove all the neutrophils thathave emigrated into the alveoli. One does wonder whetherneutrophils that cannot transform their integrins into a highactivation state might be less sticky and more lavageable than wild-type neutrophils, but the major process that activated integrinsappear to be impeding is trafficking through the interstitium.Furthermore, these studies address the effect of a b2-integrinallosteric antagonist, XVA143, that mimics the deficiency ofkindlin-3 by preventing the transformation from mid to highaffinity (12). Importantly, XVA143 also results in greater numbersof neutrophils in the interstitium and the bronchoalveolar lavagefluid. This two- to threefold increase in neutrophils does notincrease lung injury, as measured by wet-to-dry weights, oralter bacterial clearance. Studies using immortalized myeloidprogenitors differentiated toward a neutrophil phenotype showthat generation of reactive oxygen species in response toP. aeruginosa is not altered by deficiency of either talin-1 orkindlin-3, but phagocytosis is reduced by about half. Why thisdefect in phagocytosis does not result in less clearance of bacteriafrom the lungs is not clear, but perhaps sufficient numbers ofneutrophils are recruited to overcome this defect. WhetherXVA143 has therapeutic use as an enhancer of neutrophilrecruitment, perhaps during antibiotic-resistant infections, remainsto be determined.Supported by National Institutes of Health grant HL114388.Am J Respir Cell Mol Biol Vol 56, Iss 5, pp 561–562, May 2017Copyright © 2017 by the American Thoracic SocietyDOI: 10.1165/rcmb.2017-0066EDInternet address: www.atsjournals.orgEditorials 561 As with all forefront work, these studies generate newquestions. Particularly important seem questions about themechanisms through which activated b2- (or b1-) integrins areslowing neutrophil migration compared with unactivated integrins.Does this slower transit act to facilitate the sealing of theendothelium during migration of neutrophils between endothelialjunctions and to prevent leakiness? Alternatively, does the brakingeffect of activated integrins enhance endothelial or interstitialinjury during diapedesis? Careful measurements of permeabilityand insight into the differences between activated and nonactivatedintegrins will be exciting to pursue. Another way to think aboutthese next questions may be to ask, how does activation of integrinsresult in less neutrophil migration? Does the greater phagocytosisseen in neutrophils with activated integrins result in fasterclearance of the stimulus, and thus more rapid turnoff ofneutrophil migration? Or do neutrophils with activated integrinsproduce an inhibitor of neutrophil recruitment (or less neutrophilchemokines)? And do activated integrins impact on resolution ofpneumonia, when assessed at later stages? Studies examiningneutrophils lacking Skap2, which is required for binding of bothtalin-1 and kindlin-3 to b2-integrins and their activation (15),might also be interesting. The innovative and ingenious studiesreported by these investigators (12) hugely enhance our knowledgeabout neutrophil recruitment in lung disease and show thatactivating integrins isn’t always “beta” for neutrophil migration! nAuthor disclosures are available with the text of this article atwww.atsjournals.org.John C. Gomez, Ph.D.Claire M. Doerschuk, M.D.Marsico Lung Institute, Division of Pulmonary Diseases and Critical CareMedicineUniversity of North CarolinaChapel Hill, North CarolinaORCID ID: 0000-0003-2638-3321 (C.M.D.).References1. Downey GP, Worthen GS, Henson PM, Hyde DM. Neutrophilsequestration and migration in localized pulmonary inflammation:capillary localization and migration across the interalveolar septum.Am Rev Respir Dis 1993;147:168–176.2. Burns AR, Smith CW, Walker DC. Unique structural features thatinfluence neutrophil emigration into the lung. Physiol Rev 2003;83:309–336.3. Wiggs BR, English D, Quinlan WM, Doyle NA, Hogg JC, Doerschuk CM.Contributions of capillary pathway size and neutrophil deformability toneutrophil transit through rabbit lungs. J Appl Physiol (1985) 1994;77:463–470.4. Doerschuk CM, Beyers N, Coxson HO, Wiggs B, Hogg JC. Comparisonof neutrophil and capillary diameters and their relation toneutrophil sequestration in the lung. J Appl Physiol (1985) 1993;74:3040–3045.5. Gebb SA, Graham JA, Hanger CC, Godbey PS, Capen RL, DoerschukCM, Wagner WW Jr. Sites of leukocyte sequestration in the pulmonarymicrocirculation. J Appl Physiol (1985) 1995;79:493–497.6. Doerschuk CM. Mechanisms of leukocyte sequestration in inflamedlungs. Microcirculation 2001;8:71–88.7. Doerschuk CM, Winn RK, Coxson HO, Harlan JM. CD18-dependentand -independent mechanisms of neutrophil emigration in thepulmonary and systemic microcirculation of rabbits. J Immunol1990;144:2327–2333.8. Mizgerd JP, Horwitz BH, Quillen HC, Scott ML, Doerschuk CM. Effectsof CD18 deficiency on the emigration of murine neutrophils duringpneumonia. J Immunol 1999;163:995–999.9. Stadtmann A, Zarbock A. The role of kindlin in neutrophil recruitment toinflammatory sites. Curr Opin Hematol 2017;24:38–45.10. Calderwood DA, Campbell ID, Critchley DR. Talins and kindlins:partners in integrin-mediated adhesion. Nat Rev Mol Cell Biol 2013;14:503–517.11. Lefort CT, Rossaint J, Moser M, Petrich BG, Zarbock A, Monkley SJ,Critchley DR, Ginsberg MH, Fässler R, Ley K. Distinct roles for talin-1and kindlin-3 in LFA-1 extension and affinity regulation. Blood 2012;119:4275–4282.12. Wilson ZS, Ahn LB, Serratelli WS, Belley MD, Lomas-Neira J, Sen M,Lefort CT. Activated b2 integrins restrict neutrophil recruitmentduring murine acute pseudomonal pneumonia. Am J Respir Cell MolBiol 2017;56:620–627.13. Behzad AR, Chu F, Walker DC. Fibroblasts are in a position to providedirectional information to migrating neutrophils during pneumonia inrabbit lungs. Microvasc Res 1996;51:303–316.14. Walker DC, Behzad AR, Chu F. Neutrophil migration throughpreexisting holes in the basal laminae of alveolar capillaries andepithelium during streptococcal pneumonia. Microvasc Res 1995;50:397–416.15. Boras M, Volmering S, Bokemeyer A, Rossaint J, Block H, Bardel B,Van Marck V, Heitplatz B, Kliche S, Reinhold A, et al. Skap2 isrequired for b2 integrin–mediated neutrophil recruitment andfunctions. J Exp Med 2017;214:851–874.EDITORIALS562 American Journal of Respiratory Cell and Molecular Biology Volume 56 Number 5 | May 2017 

Activating integrins isn't always "beta" for neutrophil migration!

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Activating integrins isn't always "beta" for neutrophil migration!

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