Circulating Markers of Necroptosis in Acute Pancreatitis

Abstract

Objectives: Necroptosis, a programmed inflammatory cell death, is involved in the pathogenesis of acute pancreatitis (AP). We compared levels of interleukin (IL)-33 (released upon necroptosis), sST2 (soluble IL-33 receptor), MLKL, RIPK1 and RIPK3 (necroptosis executioner proteins), and proinflammatory cytokines IL-6, TNF and IL-1β at various severity categories and stages of AP.

Methods: Plasma from 20 patients with early mild AP (MAP) (symptom onset < 72 h), 7 with severe AP (SAP) without and 4 with persistent organ failure (OF) at sampling, 8 patients with late SAP and 20 healthy controls (HC) were studied by ELISAs.

Results: Early sST2 and IL-6 levels predicted the development of SAP and were higher in both MAP and early and late SAP than in HC. RIPK3 levels were higher than in HC in the patients who had or would later have SAP. MLKL levels were associated with the presence of OFs, particularly in the late phase, but were also higher in MAP than in HC.

Conclusions: sST2, RIPK3 and IL-6 levels may have prognostic value in AP. Elevated MLKL levels are associated with OF in AP. Better understanding of necroptosis in AP pathophysiology is needed to evaluate whether inhibiting and targeting necroptosis is a potential therapeutic option in AP.

Keywords: Acute pancreatitis; MLKL; Necroptosis; Organ failure; RIPK3; sST2.

Fig. 1

Patient groups in the study

Fig. 2

Plasma levels of necroptosis markers A sST2, B IL-33, C RIPK1, D RIPK3, and E MLKL, and proinflammatory cytokines, F IL-1 beta, G IL-6, and H TNF in control subjects (controls, n = 20), and patients with mild acute pancreatitis (MAP, n = 20). Severe acute pancreatitis was sampled prior to the occurrence of organ failure [(SAPOF−), n = 7] or after manifested organ failure [(SAPOF+), n = 4], or late severe acute pancreatitis [(SAPL), n = 8)]. Groups were compared by Kruskal–Wallis test, and statistically significant post hoc p-values by Mann–Whitney test are shown. Circles denote results of individual subjects, boxes denote 25th to 75th percentiles of groups, and horizontal bars inside boxes denote group medians. The lowest standard concentration is shown as a dashed line, and measured values below that are set to half of the lowest standard concentration. Note logarithmic scales in panels A, C and E–H

Fig. 3

Correlations of plasma levels of necroptosis markers sST2, IL-33, RIPK3, and MLKL with APACHEII and SOFA scores in all patients with acute pancreatitis (n = 39). Spearman correlation coefficients with 95% confidence intervals (CIs) and associated p-values are shown within figure panels. Fit lines are shown with 95% CI denoted by dotted line