IL-32γ Delays Spontaneous Apoptosis of Human Neutrophils through MCL-1, Regulated Primarily by the p38 MAPK Pathway

Abstract

IL-32γ is a multifunctional cytokine involved in various inflammatory and auto-immune diseases in which neutrophils can affect the evolution of these diseases. To persist at inflammatory sites, neutrophils require inhibition of their rapid and constitutive apoptosis, an inhibitory effect that phlogogenic cytokines support. To date, the effects of IL-32γ on neutrophils remain unknown. We demonstrate that IL-32γ delays, in a dose-dependent manner, the spontaneous apoptosis of human blood neutrophils by activating mainly p38 MAPK through rapid p38 phosphorylation. PI3-K and ERK1/2 MAPK are also involved, but to a lesser extent. Most of cytokines that induce retardation of neutrophil apoptosis activate the expression of MCL-1 at both mRNA and protein levels. IL-32γ added to human blood neutrophils in vitro is associated with sustained levels of MCL-1 protein. This effect in neutrophils corresponds to a decrease of MCL-1 protein degradation without any effect on MCL-1 mRNA levels. The sustained levels of MCL-1 induced by IL-32γ are only abrogated by the p38β MAPK inhibitor SB202190. Additionally, IL-32γ induces a reduction in caspase 3 activity in neutrophils. In conclusion, IL-32γ affects human blood neutrophils in vitro by increasing their survival, suggesting that this cytokine could have profound effects on the deleterious functions of neutrophils in several diseases.

Neutrophil Survival Signaling During Francisella tularensis Infection

“…In this regard it noteworthy that F. tularensis uses multiple strategies to disrupt NADPH oxidase assembly and activity in PMNs, and phosphorylation of p47 phox is significantly diminished ( McCaffrey et al., 2010 ; Kinkead and Allen, 2016 ). A role for p38 MAPK in prolonging PMN survival has been demonstrated in hypoxia, exposure to IL-32γ or dexamethasone and during infection with Coxiella burnetii , and we extended this list to include F. tularensis ( Klein et al., 2001 ; Saffar et al., 2008 ; Dyugovskaya et al., 2011 ; Allaeys et al., 2014 ; Cherla et al., 2018 ).…”

DataSheet_1.pdf

“…In this regard it noteworthy that F. tularensis uses multiple strategies to disrupt NADPH oxidase assembly and activity in PMNs, and phosphorylation of p47 phox is significantly diminished (McCaffrey et al, 2010;Kinkead and Allen, 2016). A role for p38 MAPK in prolonging PMN survival has been demonstrated in hypoxia, exposure to IL-32g or dexamethasone and during infection with Coxiella burnetii, and we extended this list to include F. tularensis (Klein et al, 2001;Saffar et al, 2008;Dyugovskaya et al, 2011;Allaeys et al, 2014;Cherla et al, 2018).…”