Peiseler, Moritz

Tacke, Frank

English

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2888HEPATOLOGY ELSEWHERE | Hepatology, Vol. 74, No. 5, 2021  EDITORSKathleen E. Corey, Boston, MAHarmeet Malhi, Rochester, MNAn Unexpected Line of Defense: Hepatoprotective Eosinophils in Ischemia- Reperfusion InjuryLiver transplantation is a highly successful treat-ment for patients with acute liver failure, end- stage liver disease, and primary hepatic malignancies. However, due to organ shortage, early allograft fail-ure and a concomitant rise in chronic liver diseases, the number of patients requiring liver transplantation is disproportionately higher than organs successfully transplanted. To meet the growing demand, extended criteria donor organs (e.g., older, steatotic, prolonged ischemia time) were implemented. These “marginal” organs are highly susceptible to ischemia- reperfusion injury (IRI), resulting in poor graft function and sur-vival in affected patients. Therapeutic or preventive modalities for IRI are limited, and our understand-ing of the pathogenesis is incomplete. IRI generally occurs after temporary deprivation and restoration of blood supply, resulting in ischemic organ damage and inflammation- mediated reperfusion injury. On a cellular level, ischemia causes oxidative stress, result-ing in hepatocyte death and Kupffer cell activation.(1) Reperfusion causes sterile inflammation, infiltra-tion of neutrophils, and release of pro- inflammatory cytokines. Immune regulation containing IRI still remains poorly understood. However, IRI not only occurs in iatrogenic settings such as transplantation, but also after traumatic injury, when immune regu-latory mechanisms might have developed. Thus, a deeper understanding could provide novel therapeu-tic strategies. A recent intriguing study by Ju et al. expanded our knowledge on regulatory mechanisms in IRI and identified an unexpected source of liver protection: Eosinophils rapidly invaded liver allografts of 22 transplant recipients in the first 2- 3  hours.(2) The authors recapitulated this observation in a mouse model of hepatic IRI, noting a stark increase in liver eosinophils over the first 24 hours after IRI (Fig. 1). Surprisingly, inhibiting eosinophils using antibody- mediated depletion or mice deficient in eosinophils, aggravated hepatic IRI, and increased liver necrosis and inflammatory cytokines. Mechanistically, invading eosinophils expressed high levels of the receptor sup-pression of tumorgenicity 2 (ST2), and ST2 worked in conjunction with its ligand IL- 33 to mediate protection. Both ST2- deficient and IL- 33- deficient mice failed to recruit eosinophils after IRI and con-sequently exhibited a higher degree of liver damage. Eosinophils are known to produce the Th2 cytokines IL- 4 and IL- 13. In expanding the mechanistic details, the authors specifically depleted either IL- 4 or IL- 13 in eosinophils using IL- 4/IL- 13fl/fl x eoCre+/x mice, which were subjected to IRI. Although blocking IL- 4 had no effect, specifically ablating IL- 13 in eosino-phils increased liver necrosis and thus failed to provide eosinophil- mediated protection. Finally, the authors noted a reciprocal relationship between eosinophils and neutrophils. Mice deficient in eosinophils had greatly increased numbers of neutrophils and increased liver damage, suggesting a regulatory role for eosino-phils by containing unhinged neutrophil recruitment.The therapeutic potential of eosinophils, the ST- 2/IL- 33 axis, and subsequent release of IL- 13 was further investigated. In a set of adoptive transfer experiments, eosinophil- mediated protection was transferable by pre- emptively administering bone marrow– derived eosinophils to eosinophil- deficient mice. Additional protection was also achieved in wild- type mice after transfer of bone marrow– derived eosinophils before IRI. Interestingly, in IL- 33 deficient mice, only IL- 33- stimulated eosinophils dampened liver injury, indicating IL- 33 was required to initiate eosinophil- mediated protection. Finally, recombinant IL- 13 given therapeutically reduced IRI in mice. In sum-mary, this study identified a hitherto unknown role for eosinophils as regulatory cells, producing IL- 13 through the ST- 2/IL- 33 axis to attenuate liver injury (Fig. 1). Importantly, the authors demonstrated a ben-eficial effect by adoptively transferring eosinophils or by administering IL- 13 in preclinical models of IRI, laying the groundwork for future translational studies aimed at improving transplant- induced IRI.Eosinophils are leukocytes typically known as cytotoxic effector cells in allergic inflammation and  15273350, 2021, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31895 by Charité - Universitaetsmedizin, Wiley Online Library on [25/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseHepatology, Vol. 74, No. 5, 2021 HEPATOLOGY ELSEWHERE2889parasitic infection. Eosinophils promote inflamma-tion through secretion of cytokines and release of toxic granules, thereby stimulating immune cell traf-ficking and function.(3) However, the ‘traditional view’ of eosinophils as destructive effector cells is evolving, and more recent studies demonstrate various regula-tory properties by promoting injury resolution through release of anti- inflammatory cytokines or direct inhibi-tion of effector cells.(4) With regard to liver injury and repair, eosinophils were shown to stimulate hepatocyte proliferation after toxic injury and partial hepatectomy by producing IL- 4 and signaling through the IL- 4 receptor on hepatocytes.(5) Along those lines, the study by Ju et al. now identifies eosinophils as hepatopro-tective cells in liver IRI and emphasizes the immune- regulatory effects of eosinophil- released IL- 13.(2) Whether eosinophil- derived IL- 13 also contributes to liver regeneration after IRI by directly stimulating hepatocyte proliferation remains unknown.This serendipitous observation is intriguing and offers therapeutic potential in transplant- induced IRI; however, a few issues need to be considered. First, eosin-ophils in the livers of transplant recipients were assessed during cold ischemia (before IRI) and after transplanta-tion (following IRI), but not compared against baseline and thus might have been artificially decreased by cold preservation. Second, while eosinophils and neutrophils showed reciprocal recruitment kinetics in mice, the pre-cise mechanism by which eosinophils or eosinophil- derived IL- 13 inhibited neutrophil recruitment remains obscure. Of note, an inhibiting role of IL- 13 on neu-trophil recruitment was previously described in hepatic Schistosomiasis.(6) Furthermore, in allergic inflammation, where Th2- type cytokines such as IL- 4 and IL- 13 FIg. 1. Eosinophils accumulate in IRI and attenuate liver damage. Eosinophils rapidly increase in liver allografts (A) and in mice subjected to experimental IRI (B). Mice deficient in eosinophils showed increased neutrophils and liver injury. (C) IL- 33 released during injury signals via ST2 on eosinophils to induce IL- 13 liberation, in turn inhibiting neutrophil recruitment and neutrophil- derived oxidants.A Liver transplantationCold ischemia ReperfusionLiver eosinophilsCEosinophilsIRIIL-33ST2ST2IL-13NeutrophilsoxidantsLiver eosinophils Liver neutrophilsLiver necrosisInflammatory cytokinesEosinophil deficient miceWild type miceExperimental ischemia-reperfusion injuryB 15273350, 2021, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31895 by Charité - Universitaetsmedizin, Wiley Online Library on [25/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseHepatology, November 2021HEPATOLOGY ELSEWHERE2890predominate, neutrophils are conspicuously absent. A number of recent studies have uncovered a reciprocal regulation of type II immune responses and neutrophil recruitment, identifying a checkpoint pathway to pre-vent excessive tissue injury.(7) Accordingly, neutrophil egress and chemotaxis was directly curtailed by IL- 4/IL- 13 signaling through type I and type II IL- 4 recep-tors on neutrophils.(7) This compelling regulatory loop might explain the findings in hepatic IRI, but more evi-dence is necessary to understand the balance between neutrophils and eosinophils. Furthermore, the authors quantified liver injury only during the first 24  hours after IRI. While often associated with tissue damage, the view of neutrophils as unrestrained cytotoxic cells is changing, and they are emerging as cells with important repair properties.(8) In various liver injury models, it was shown that early neutrophil depletion was accompanied by smaller injury size yet translated into defective heal-ing after a few days.(8) Thus, it is worthwhile investi-gating whether reduced neutrophil recruitment early has inauspicious effects at later stages. An additional point worth raising is that the mouse model of IRI only par-tially mimics IRI in liver transplantation, and by tempo-rarily clamping blood flow, causes retrograde blood stasis in the intestine, leading to barrier disruption and leaky gut. Ju et al. found IL- 33 as the main cytokine to induce the eosinophil- driven protection, yet the source of IL- 33 was unknown. IL- 33 is an “alarmin” that is released by different cells such as endothelial and epithelial cells in a variety of tissue perturbations; thus, an additional source of IL- 33 in hepatic IRI could be the perturbed intestine. IL- 33 mediates an array of immune modulatory proper-ties, primarily through ST2 on regulatory immune cells, such as regulatory T cells and innate- like lymphocytes 2 (ILC2s).(2) Although the authors demonstrated that eosinophils were the most abundant ST2- expressing cells in the liver, regulatory T cells and ILC2s might still account for some of the protective effect, either directly in the liver or systemically through IL- 33.Hepatic IRI is an important iatrogenic sequela, and most experimental studies have focused on the ensuing effector cells causing hepatocellular dam-age. However, rather than diminishing the effector arm, balance might be therapeutically restored by strengthening regulatory immunity. As such, the study by Ju et al. provides pioneering evidence for an overlooked cell type: protective eosinophils that rapidly invade the liver, skewing the microenviron-ment toward repair by releasing IL- 13 and hopefully spawning future studies investigating the therapeu-tic potential of eosinophils.Acknowledgment: Figure 1 was created with BioRender.com.Moritz Peiseler, M.D.1,2  Frank Tacke, M.D., Ph.D.11 Department of Hepatology & GastroenterologyCharité Universitätsmedizin BerlinCampus Virchow- Klinikum and Campus Charité MitteBerlin, Germany2 Berlin Institute of Health, Berlin, GermanyReFeReNCeS 1) Dar WA, Sullivan E, Bynon JS, Eltzschig H, Ju C. Ischaemia reper-fusion injury in liver transplantation: cellular and molecular mecha-nisms. Liver Int 2019;39:788- 801. 2) Wang y, yang y, Wang M, Wang S, Jeong J- M, Xu L, et al. Eosinophils attenuate hepatic ischemia- reperfusion injury in mice through ST2- dependent IL- 13 production. Sci Transl Med 2021;13:eabb6576. 3) Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol 2006;24:147- 174. 4) Lee JJ, Jacobsen EA, McGarry MP, Schleimer RP, Lee NA. Eosinophils in health and disease: the LIAR hypothesis. Clin Exp Allergy 2010;40:563- 575. 5) goh ypS, Henderson NC, Heredia JE, Eagle AR, Odegaard JI, Lehwald N, et al. Eosinophils secrete IL- 4 to facilitate liver regen-eration. Proc Natl Acad Sci U S A 2013;110:9914- 9919. 6) Seki T, Kumagai T, Kwansa- Bentum B, Furushima- Shimogawara R, Anyan WK, Miyazawa Y, et al. Interleukin- 4 (IL- 4) and IL- 13 suppress excessive neutrophil infiltration and hepatocyte dam-age during acute murine schistosomiasis japonica. Infect Immun 2012;80:159- 168. 7) egholm C, Heeb leM, Impellizzieri D, Boyman O. The regu-latory effects of interleukin- 4 receptor signaling on neutrophils in type 2 immune responses. Front Immunol 2019;10:2507. 8) Peiseler M, Kubes P. More friend than foe: the emerging role of neutrophils in tissue repair. J Clin Invest 2019;129:2629- 2639.Author names in bold designate shared co- first authorship.Supported by the German Research Foundation (SFB/TRR296, CRC1382, Ta434/3- 1, and Ta434/5- 1) and the Berlin Institute of Health (BIH- Charité Clinician Scientist Program) funded by the Charité– Universitätsmedizin Berlin and the Berlin Institute of Health.© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modif ications or adaptations are made.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.31895Potential conflict of interest: Nothing to report. 15273350, 2021, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31895 by Charité - Universitaetsmedizin, Wiley Online Library on [25/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

An Unexpected Line of Defense: Hepatoprotective Eosinophils in Ischemia‐Reperfusion Injury

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An Unexpected Line of Defense : Hepatoprotective Eosinophils in Ischemia‐Reperfusion Injury

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An Unexpected Line of Defense: Hepatoprotective Eosinophils in Ischemia‐Reperfusion Injury

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