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What Doesn’t Kill You Makes You Stronger: The Anti-inflammatory Effect of Respiratory Burst

Niels Borregaard1,* 1Department of Hematology, National University Hospital, University of Copenhagen, 2100 Copenhagen, Denmark *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2013.12.003

In this issue of Immunity, Campbell et al. (2014) demonstrate that hypoxia caused by the respiratory burst of infiltrating activates hypoxia inducible factor (HIF) in epithelial cells and protects the mucosa cells in an experimental model of inflammatory bowel disease.

Neutrophils have long been recognized as oxygen on the outside of the or ratory burst, survive after a few days of critical for defense against microbial inside the phagosomal vacuole. The incapacitation. . Although a normal supply of primary product, anions, How can the paradigm of how neutro- neutrophils is important, numbers are dismutate to oxygen and hydrogen phils interact with the tissues suddenly not all that is needed. The neutrophils peroxide, which in turn can be acted be turned completely around? Elemen- must also migrate into tissues. Leukocyte on by a major constituent of neutrophil tary, my dear Watson: by looking at the adhesion deficiencies, of which three primary granules, , for substrate, oxygen rather than the prod- forms exist, are associated with major the generation of , uct, . and often life-threatening infections which has a broad and potent antimicro- Campbell et al. (2014) noticed that caused by the inability of neutrophils to bial effect (Rosen et al., 2002). Although neutrophils that migrate across epithelial migrate from the blood to tissues to there are still some controversies as to cells change the mRNA expression pro- meet the microbes (Harris et al., 2013). the role these reactive oxygen species file of the epithelial cells, which upregu- That severe gastrointestinal infections play in bacterial killing (Segal, 2005), late genes responding to hypoxia. A are common in such patients is easy to it has long been recognized that the priori, this change would seem to be comprehend, because our gastrointes- activity of this NADPH oxidase, which most likely caused by the intimate con- tinal tract houses myriads of microbes, can be monitored as net consumption tact between transepithelial migrating many of which could potentially enter of oxygen using an oxygen electrode, is neutrophils and the epithelial cells. How- our tissues were it not for an effective dramatic and rightfully termed the re- ever, the same effect could be observed barrier provided by mucus produced by spiratory burst of . The when neutrophils were incubated with, goblet cells (Hansson, 2012) and anti- lack of respiratory burst is the hallmark but physically separated from, the bacterial activity provided by epithelial of CGD and is associated with severe epithelial cells, and the effect is thus cells (Ramasundara et al., 2009) and immunodeficiency. caused by factors present in the medium neutrophils. Although neutrophils are essential for in which the neutrophils were incubated. Neutrophil recruitment to tissues such our health, they are also implicated in Again, a priori, factors secreted by the as the gastrointestinal tract is not suffi- the pathophysiology of several chronic neutrophil would seem the likely cause, cient to provide optimal protection. The inflammatory diseases. Untoward recruit- because neutrophils are cells capable of neutrophils must be capable of executing ment and activation of neutrophils secreting several proteases that might a full antimicrobial attack as exemplified participate in destruction of tissue in rheu- trigger receptors on epithelial cells, but by the rare but severe condition now matoid arthritis and chronic obstructive no, such is not the case. The factor termed chronic granulomatous disease pulmonary disease and in inflammatory responsible for this effect is not some- (CGD) but initially named fatal granuloma- bowel disorders such as ulcerative colitis thing present in the medium, but some- tous disease of childhood to underscore and Crohn’s disease. thing (almost) absent from the medium: the severity of this inheritable condition In this issue of Immunity, Campbell and oxygen (Figure 1). (Holland, 2013). colleagues convincingly demonstrate that The observation is validated in vivo When neutrophils sense the respiratory burst of neutrophils, long in a model of inflammatory bowel dis- or mediators of inflammation, they as- perceived as proinflammatory, in fact ease where inflammation is induced semble an electron transport chain in plays a major anti-inflammatory role and chemically by trinitrobenzenesulfonic their surface membrane and phago- causes major reduction of inflammation acid (TNBS). This causes a self-limiting somal membrane. This electron chain, in a mouse model of inflammatory bowel inflammation with brisk neutrophil re- known as the NADPH oxidase, shuffles disease. They show that CGD mice suc- cruitment in the gut. Hypoxia of the gut electrons across these membranes cumb, whereas mice with wild-type (WT) epithelial cells is monitored in vivo as from NADPH in the cytosol to molecular neutrophils, capable of mounting a respi- these mice were genetically modified to

Immunity 40, January 16, 2014 ª2014 Elsevier Inc. 1 Immunity Previews

transgenic with respect to HIF-induced that might contribute in addition to hypox- luciferase activation and are incapable ia to the differences in inflammation be- of mounting a neutrophil respiratory tween the CGD mice and WT mice. The burst, i.e., CGD mice, responded with a message is, however, still clear: We severe and deadly inflammation, but must rethink our strategy for ameliorating no increase in HIF. Thus, absence of inflammation and go for a hypoxia neutrophils worsens tissue destruction response instead of inhibiting neutrophil and the presence of neutrophils inca- recruitment and activation. pable of consuming oxygen makes it even worse. In both cases, the tissue REFERENCES destruction and the survival of the mice was greatly improved by artificially Campbell, E.L., Bruyninckx, W.J., Kelly, C.J., raising HIF even though oxygen was Glover, L.E., McNamee, E.N., Bowers, B.E., Bay- present. As the authors demonstrated, less, A.J., Scully, M., Saeedi, B.J., Golden-Mason, L., et al. (2014). Immunity 40, this issue, 66–77. Figure 1. Hypoxia Induced by Activated hypoxia-induced HIF activation elicits Neutrophils Protects Epithelial Cells a protective response in the epithelial Hansson, G.C. (2012). Curr. Opin. Microbiol. 15, Activated neutrophils (N) infiltrate the mucus 57–62. membrane during gastrointestinal inflammation. cells such as increased mucin pro- NADPH oxidase activity consumes oxygen for duction and a better barrier function Harris, E.S., Weyrich, A.S., and Zimmerman, G.A. 20 production of reactive oxygen species H2O2 and against microorganisms, and higher (2013). Curr. Opin. Hematol. , 16–25. hypochlorous acid, OClÀ. The resulting lowering of oxygen tension in epithelial cells (E) indicated amounts of resolving lipids such as Holland, S.M. (2013). Hematol. Oncol. Clin. North 27 by darker shading results in increased levels of Resolvin D1 and 15-epi-Lipoxin A4. Am. , 89–99, viii. hypoxia inducible factor (HIF), a transcription Interestingly, hypoxia itself is known to Ramasundara, M., Leach, S.T., Lemberg, D.A., factor that activates transcription of genes that prolong the lifetime of neutrophils by and Day, A.S. (2009). J. Gastroenterol. Hepatol. result in protection of the mucosal cells and re- 24, 202–208. duces inflammation. HIF activation (Walmsley et al., 2011), thus creating a positive feedback loop Ratcliffe, P.J. (2013). J. Physiol. 591, 2027–2042. for this process. light up when hypoxia inducible factor Finally, biopsies taken from patients Rosen, H., Crowley, J.R., and Heinecke, J.W. (2002). J. Biol. Chem. 277, 30463–30468. (HIF) is high, i.e., when the oxygen with inflammatory bowel disease demon- tension, which this factor carefully moni- strated that HIF activation is indeed char- Segal, A.W. (2005). Annu. Rev. Immunol. 23, tors (Ratcliffe, 2013), is low. The first acteristic of the lesions where neutrophil 197–223. important observation was that deplet- infiltration is prominent. ing neutrophils worsened the inflamma- The authors do not address older Voetman, A.A., Weening, R.S., Hamers, M.N., Meerhof, L.J., Bot, A.A.A.M., and Roos, D. (1981). tion but did not cause the gut epithelium observations (Voetman et al., 1981) J. Clin. Invest. 67, 1541–1549. to light up. Thus, hypoxia was not demonstrating that the products of the induced by the severe perturbation of respiratory burst, such as hypochlorous Walmsley, S.R., Chilvers, E.R., Thompson, A.A., Vaughan, K., Marriott, H.M., Parker, L.C., Shaw, the epithelial lining. The second obser- acid, inactivate secreted proinflammatory G., Parmar, S., Schneider, M., Sabroe, I., et al. vation was that mice which are both products of neutrophils, a phenomenon (2011). J. Clin. Invest. 121, 1053–1063.

2 Immunity 40, January 16, 2014 ª2014 Elsevier Inc.