The Dual Role of Neutrophils in Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of immunity, clearly separate them. Neutrophils are the first immune cells recruited to the site of inflammation, and their action is crucial to limit invasion by microorganisms. Furthermore, they play an essential role in proper resolution of inflammation. When these processes are not tightly regulated, they can trigger positive feedback amplification loops that promote neutrophil activation, leading to significant tissue damage and evolution toward chronic disease. Defective chemotaxis, as observed in Crohn's disease, can also contribute to the disease through impaired microbe elimination. In addition, through NET production, neutrophils may be involved in thrombo-embolic events frequently observed in IBD patients. While the role of neutrophils has been studied in different animal models of IBD for many years, their contribution to the pathogenesis of IBD remains poorly understood, and no molecules targeting neutrophils are used and validated for the treatment of these pathologies. Therefore, it is crucial to improve our understanding of their mode of action in these particular conditions in order to provide new therapeutic avenues for IBD.

Keywords: hyper-activation; intestinal inflammation; neutrophils; therapy.

Figure 1

Dual role of neutrophils in intestinal inflammation. Excessive or prolonged neutrophil activation can lead to chronic inflammation in inflammatory bowel disease (IBD). Reactive oxygen species (ROS) production causes damage to DNA, lipids and proteins, altering their function. Paradoxically, ROS is also essential for the maintenance of intestinal homeostasis. Upon neutrophil activation, some proteases such as elastase, MMP-8 or MMP-9 are produced, leading to structural tissue damage and amplification of the inflammatory response through release of pro-inflammatory cytokines and chemokines from extra-cellular matrix (ECM). The enzyme 5-lipoxigenase (5-LO) is involved in the synthesis pro-inflammatory lipid mediators like LTB₄ as well as in the production of pro-resolving lipid mediator generation, including lipoxin A₄, resolvin E₁ and protectin D₁, during the resolution of inflammation. Annexin A₁ is expressed by apoptotic neutrophils and triggers neutrophil apoptosis, neutrophil engulfment by macrophages and negatively regulates neutrophil transmigration. Finally, neutrophils can be responsible for increased risk of thrombosis in IBD through neutrophil extracellular traps (NET) release. Abbreviations: Nox: NADPH oxidase; ROS: reactive oxygen species; MPO: myeloperoxidase; MMP: matrix metalloprotease; LTB₄: leukotriene B₄; NETs: neutrophil extracellular traps.