RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils.

Suguru Saito,Zhenzi Peng,Hui-Ya Wu,Derick Okwan-Duodu,Aaron R Victor,Duo-Yao Cao

doi:10.3389/fimmu.2021.744300

Abstract

As first responder cells in host defense, neutrophils must be carefully regulated to prevent collateral tissue injury. However, the intracellular events that titrate the neutrophil’s response to inflammatory stimuli remain poorly understood. As a molecular switch, Ras activity is tightly regulated by Ras GTPase activating proteins (RasGAP) to maintain cellular active-inactive states. Here, we show that RASAL3, a RasGAP, is highly expressed in neutrophils and that its expression is upregulated by exogenous stimuli in neutrophils. RASAL3 deficiency triggers augmented neutrophil responses and enhanced immune activation in acute inflammatory conditions. Consequently, mice lacking RASAL3 (RASAL3-KO) demonstrate accelerated mortality in a septic shock model via induction of severe organ damage and hyperinflammatory response. The excessive neutrophilic hyperinflammation and increased mortality were recapitulated in a mouse model of sickle cell disease, which we found to have low neutrophil RASAL3 expression upon LPS activation. Thus, RASAL3 functions as a RasGAP that negatively regulates the cellular activity of neutrophils to modulate the inflammatory response. These results demonstrate that RASAL3 could serve as a therapeutic target to regulate excessive inflammation in sepsis and many inflammatory disease states.

Highlights

Ras signaling is an indispensable biological process that shapes cell proliferation, differentiation, and activation, allowing cells to respond to environmental cues and maintain homeostasis [1, 2]
Because tissue microenvironment has been shown to affect neutrophil transcriptional phenotype [21], we sought to determine if tissue of origin played a role in neutrophil RASAL3 expression
Addressing this knowledge gaps is crucial for the comprehensive understanding of mechanisms to tone down inflammation, the extent of which may lead to collateral tissue damage and mortality, as occurs in sepsis [28]

Summary

Introduction

Ras signaling is an indispensable biological process that shapes cell proliferation, differentiation, and activation, allowing cells to respond to environmental cues and maintain homeostasis [1, 2]. In response to external stimuli, Ras is converted from its inactive form (Ras-GDP) to its active form (Ras-GTP) by guanine nucleotide exchange factors (GEF) [3]. Active Ras-GTP transmits the external signal via the mitogen-activated protein kinase (MAPK) pathway comprising Raf, mitogenactivated protein kinase kinase 1 (MEK), and extracellular signal-regulated kinase (Erk) [4]. Ras signaling activates other factors such as Akt and p38MAPK [5]. While activation of the Ras signaling pathway is critical for cellular response to environmental cues, inactivation is required for RASAL3 Regulates Neutrophil Inflammatory Response the maintenance of homeostasis. Failure to suppress overactivation of Ras signaling leads to dysfunction and disease, including excess inflammation and tumorigenesis [3, 6]

Methods

Results

Conclusion