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Regulation of inflammation by the antioxidant haem oxygenase 1

Abstract

Haem oxygenase 1 (HO-1), an inducible enzyme responsible for the breakdown of haem, is primarily considered an antioxidant, and has long been overlooked by immunologists. However, research over the past two decades in particular has demonstrated that HO-1 also exhibits numerous anti-inflammatory properties. These emerging immunomodulatory functions have made HO-1 an appealing target for treatment of diseases characterized by high levels of chronic inflammation. In this Review, we present an introduction to HO-1 for immunologists, including an overview of its roles in iron metabolism and antioxidant defence, and the factors which regulate its expression. We discuss the impact of HO-1 induction in specific immune cell populations and provide new insights into the immunomodulation that accompanies haem catabolism, including its relationship to immunometabolism. Furthermore, we highlight the therapeutic potential of HO-1 induction to treat chronic inflammatory and autoimmune diseases, and the issues faced when trying to translate such therapies to the clinic. Finally, we examine a number of alternative, safer strategies that are under investigation to harness the therapeutic potential of HO-1, including the use of phytochemicals, novel HO-1 inducers and carbon monoxide-based therapies.

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Fig. 1: HO-1 and haem catabolism.
Fig. 2: Regulation of HO-1 expression.
Fig. 3: Immunoregulation by the HO-1 system.

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Acknowledgements

The authors acknowledge support from the Health Research Board (ILP-POR-2017-041), Ireland.

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N.K.C, H.K.F and A.D conceptualized the article. N.K.C and H.K.F prepared the manuscript and figures together. All authors contributed equally to the revision and editing of the submitted article.

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Correspondence to Nicole K. Campbell.

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Nature Reviews Immunology thanks E. Bruscia, C. Di Pietro, J. S. Lee and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Porphyrin

An organic molecule comprising four pyrrole rings connected to form a larger ring structure, which readily binds metal ions. Iron-containing porphyrins are known as ‘haems’.

‘M2-like’ macrophage

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with interferon-γ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Haemin

An endogenously produced haem molecule containing a chloride ion. Haemin is also available as a purified product from mammalian red blood cells, which is used both in research as an inducer of haem oxygenase 1 (HO-1) and in medicine as a treatment for porphyria.

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Campbell, N.K., Fitzgerald, H.K. & Dunne, A. Regulation of inflammation by the antioxidant haem oxygenase 1. Nat Rev Immunol 21, 411–425 (2021). https://doi.org/10.1038/s41577-020-00491-x

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