Inhibition of pyrimidine synthesis in murine skin wounds induces a pyoderma gangrenosum-like neutrophilic dermatosis accompanied by spontaneous gut inflammation

Abstract

Pyoderma gangrenosum (PG) is a debilitating skin condition often accompanied by inflammatory bowel disease (IBD). Strikingly, ~40% of patients that present with PG have underlying IBD, suggesting shared but unknown pathogenesis mechanisms. Impeding the development of effective treatments for PG is the absence of an animal model that exhibits features of both skin and gut manifestations. This study describes the development of the first experimental drug-induced mouse model of PG with concurrent intestinal inflammation. Topical application of pyrimidine synthesis inhibitors on wounded mouse skin generates skin ulcers enriched in neutrophil extracellular traps (NETs) and pro-inflammatory cellular as well as soluble mediators mimicking human PG. The mice also develop spontaneous intestinal inflammation demonstrated by histologic damage. Further investigations revealed increased circulating immature low-density IL-1β primed granulocytes that undergo enhanced NETosis at inflamed tissue sites supported by increase in circulatory citrullinated histone 3, a marker of aberrant NET formation. Granulocyte depletion dampens the intestinal inflammation in this model, further supporting the notion that granulocytes contribute to the skin-gut crosstalk in PG mice. We anticipate that this novel murine PG model will enable researchers to probe common disease mechanisms and identify more effective targets for treatment for PG patients with IBD.

What can inherited immunodeficiencies reveal about pyoderma gangrenosum?

“…Given emerging cases of primary immunodeficiency‐associated PG, the question of possible genetic predisposition to the development of PG may be raised. It has been suggested that elevated levels of pro‐inflammatory cytokines may serve as a second hit in the development of PG‐like inflammation caused by neutrophil extracellular trap (NET) formation 85 . It is interesting to consider whether the development of PG requires acquisition of a second pro‐inflammatory hit, and whether patients who have a primary immunodeficiency are more susceptible to developing PG due to an existing aberration.…”

“…It has been suggested that elevated levels of pro-inflammatory cytokines may serve as a second hit in the development of PG-like inflammation caused by neutrophil extracellular trap (NET) formation. 85 It is interesting to consider whether the development of PG requires acquisition of a second pro-inflammatory hit, and whether patients who have a primary immunodeficiency are more susceptible to developing PG due to an existing aberration. Further studies detailing the natural history of the disease as well as studies involving the inflammatory mechanisms of PG may prove useful in determining whether the inflammatory pathways and NETosis involved in PG require a second hit.…”

Understanding multi‐kinase inhibitor‐associated cutaneous ulcers may provide molecular insights into the aetiology of pyoderma gangrenosum: A comment on Jeon et al.

“…Dear Editor, Pyoderma gangrenosum (PG) is a chronic, ulcerative skin condition characterised by dysregulated responses of neutrophils, T cells, macrophages and fibroblasts to antigenic stimuli. 1 Our understanding of the aetiology of PG to guide targeted therapeutics has been hindered by a lack of validated animal models, with a murine skin model only recently established by Jatana et al 2 While this model is a valuable first step, this was only validated against known inflammatory cytokine/chemokine profiles of PG and has, therefore, not yet been used to discover novel molecular characteristics. As such, drug-induced PG remains a useful model to improve the understanding of PG pathophysiology via deciphering the molecular actions of causative medications.…”