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What good can neutrophils do in UC?

Neutrophils are essential for limiting the translocation of bacteria when mucosal surfaces are breached. Among other antimicrobial mechanisms, neutrophils can release neutrophil extracellular traps (NETs), which are weblike extracellular structures containing cytosolic and granule proteins assembled on a network of decondensed chromatin. Formation of NETs is dependent on the activity of peptidylarginine deiminases (PAD), in particular, PAD4, an enzyme that catalyses the citrullination of histones and promotes chromatin decondensation. While limiting bacterial and fungal dissemination, NETs—like other neutrophil effector mechanisms—can contribute to the pathogenesis of immunemediated diseases, including UC. The ability of NETs to damage tissues is well documented in infection and sterile disease. Indeed, previous evidence has shown the beneficial effects of PAD4 inhibitors, or of treatment with DNAse, in models of colitis, making these molecules attractive new targets with antiinflammatory potential. In Gut, Leppkes and collaborators contradict this dogma and describe the unexpected protective role of those NETs that participate in homeostasis and reduce the bleeding of intestinal ulcers. This effect is dependent on the activity of PAD4, as shown by PAD4deficient mice, which suffer from increased mucosal damage and disease severity in experimental models of wound healing and colitis. These results, which challenge the previous hypothesis that neutrophils and, in particular, the formation of NETs can contribute to disease worsening and impair mucosal healing, should prompt a reexamination of the longheld ‘bad reputation’ that neutrophils have in association with UC. As a matter of fact, there is accumulating evidence that would support alternative roles for neutrophils in several immunemediated diseases. Indeed, the formation of NETs by neutrophils has been implicated in the resolution of inflammation in noninfectious damage, including myocardial infarction. In particular, this study shows a role for NETs in driving the differentiation of alternatively activated macrophages, in suppressing proinflammatory macrophages, and in inducing transforming growth factor beta (TGF-β) expression by fibroblasts. In addition, neutrophils are also thought to play roles both in wound repair and in the resolution of inflammation. Mice deficient in CXCR2, a chemokine receptor implicated in monocyte and neutrophil recruitment, showed significant delays in wound healing, including epithelialisation and neovascularisation, after skin wounding. While a role for CXCR2expressing keratinocytes is also described in this study, the results support the clear involvement of neutrophil and monocyte recruitment within the wound bed in skin repair. Other direct effects of neutrophils on intestinal wound healing have also been noted. For instance, the binding of neutrophils to epithelial monolayers has been shown to promote epithelial cell proliferation and overall epithelial homeostasis. These are accomplished by diverse mechanisms including release of adenosine and extracellular vesicles as well as induction of a hypoxic gene signature that stabilises expression of the hypoxiainducible factor, which drives the upregulation of mucins, antibacterial peptides and trefoil factors by epithelial cells. In addition to promoting healing by themselves, neutrophils can influence the behaviour of other cells that are essential for the resolution of inflammation. For example, following phagocytosis of apoptotic neutrophils, a process known as efferocytosis, macrophages shift to a repair phenotype that produces TGF-β and IL10. Similar to the heterogeneity described among tissue macrophages, more recent studies demonstrate that neutrophils can also acquire alternative phenotypes. Indeed, two types of neutrophils, N1 and N2, were initially described in cancer. Signals from the tumour microenvironment were thought to promote the polarisation of neutrophils towards an N1 antitumourigenic or N2 protumour phenotype. However, unlike M1 and M2, to date, there is no suitable marker to distinguish N1 and N2 neutrophils in tumours. Regardless of their different phenotypes, the role played by neutrophils in tumour progression is, indeed, an emerging area of interest that deserves further attention. Beyond cancer, heterogeneity in neutrophil populations has also been described in other diseases including sterile inflammation, ischaemic damage and autoimmunity. Roles in both immunosuppression and angiogenesis have been attributed to neutrophils. In fact, N1like proinflammatory neutrophils are rapidly recruited to the ischaemic myocardium in mice and express a clear inflammatory cytokine pattern. However, this initial influx is followed by a surge in N2 antiinflammatory neutrophils (expressing Arg1, IL10 and Ym1, genes that are also regulated by M2, an antiinflammatory macrophage). One of the few studies to have suggested a potentially protective neutrophil population in IBD describes a population identified by CD177 expression, which exerts a dual role in microbial defence while promoting epithelial barrier integrity. Though producing hydrogen peroxide and reactive oxygen species, CD177+ neutrophils showed a lower secretion of proinflammatory cytokines, but higher levels of IL22 and TGF-β, compared with the CD177population. In addition, mice lacking CD177 showed a compromised intestinal barrier and developed more severe colitis, in response to dextran sodium sulfate, compared with wildtype mice. Another distinct population thought to play a role in cancer development and inflammation is a proangiogenic neutrophil population that has been identified in humans. This population not only responds to and produces vascular endothelial growth factor A (VEGFA) but also expresses the chemokine receptor CXCR4. Unpublished data from our lab also show that this population can be found within the colonic inflamed mucosa of patients with UC(GarridoTrigo A et al). However, its role and potential implications in UC disease activity and/or resolution have not been yet determined. Thus, beyond their wellknown involvement in limiting microbial invasion during infection, accumulating data shows that neutrophils can promote immunosuppression, angiogenesis and tissue repair in sterile tissue damage and autoimmunity. These distinct functions are thought to be supported by alternatively activated neutrophil populations, including subsets with angiogenic, immunosuppressive and/ or epithelial protecting subtypes, which have yet to be characterised in UC. Studies that unravel the potential heterogeneity in mucosal neutrophil populations and allow for specific targeting of some neutrophilmediated function, while still preserving others, are urgently required. IDIBAPS, CIBERehd, Hospital Clinic de Barcelona, Barcelona, Spain