Aberrant Neutrophil Trafficking and Metabolic Oscillations in Severe Pyoderma Gangrenosum

Abstract

Having previously associated metabolic oscillations with cell locomotion, we hypothesized that patients with abnormalities in neutrophil trafficking may display aberrant intracellular oscillations. A pyoderma gangrenosum patient exhibiting aberrant leukocyte trafficking in vivo and skin ulceration without infection was identified. This patient's neutrophils constitutively overexpressed and clustered the leukocyte integrins CR3 and CR4 and failed to display appropriate integrin-to-GPI receptor interactions. Increased levels of tyrosine phosphorylation were observed. NAD(P)H oscillations, which are sinusoidal in normals, were chaotic with multiple frequency components in this patient's neutrophils. Normal cell shape and sinusoidal NAD(P)H oscillations were restored by providing a pulsed electric field to drive metabolic oscillations and by temperature reduction. N-acetyl-D-glucosamine disrupted CR3 clusters and sinusoidal NAD(P)H oscillations returned. Anecdotal reports suggest that local hypothermia is clinically useful for this patient. These data define the first metabolic oscillation-associated disease and suggest that pyoderma gangrenosum can be classified as a dynamical disease at the cellular level.

RETRACTED: Dissipative metabolic patterns respond during neutrophil transmembrane signaling

“…This autofluorescence has been linked with neutrophil NAD(P)H, metabolism, function, and disease (7,8,19,(23)(24)(25)(26). Thus, NAD(P)H fluorescence was used as a convenient means of following intracellular metabolism in living cells and metabolic responses to receptor ligation.…”

“…For example, cell functions driven by electron transfer from NADPH such as superoxide and NO production are in phase with NADPH oscillations and reflect the frequency and amplitude of these oscillations (6-8, 20, 24, 39). Indeed, defects in metabolic oscillations have been associated with certain deficiencies in neutrophil function (25,26). Thus, these dissipative temporal oscillations are associated with cell functions.…”

Ebola Virus Secretory Glycoprotein (sGP) Diminishes FcγRIIIB-to-CR3 Proximity on Neutrophils

“…These interactions have been observed by a variety of techniques including cocapping, RET, lateral diffusion, immunoprecipitation, gene transfection, and gene knock-out experiments (5-9, 15, 16, 20 -23). Clinical aberrations in these interactions have also been observed in neutrophils from certain pyoderma gangrenosum patients (24,25). These studies suggest a potential mechanism that accounts for transmembrane signaling by certain GPI-anchored receptors.…”

Management of pyoderma gangrenosum

“…Neutrophil trafficking abnormalities have been observed, which may be due to alterations in expression of cell surface integrins CR3 and CR4 and inappropriate integrin-receptor interactions, along with increased metabolic oscillations, responsible for cell locomotion. 10 Immunohistochemistry of skin specimens from PG ulcers demonstrates high expression of myeloperoxidase, a neutrophil marker, and of interleukin-8 (IL-8), a potent chemoattractant that recruits neutrophils to sites of infection. In human skin xenografts, IL-8 overexpression induced subepidermal neutrophil accumulation and formation of ulcers resembling PG clinically and histologically.…”