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PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury.

ABSTRACT: Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.

SUBMITTER: Du X

PROVIDER: S-EPMC10825202 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury.

Du Xinyue X Ren Baiyang B Li Chang C Li Qi Q Kan Shuo S Wang Xin X Bai Wenjuan W Wu Chenyun C Kassegne Kokouvi K Yan Huibo H Niu Xiaoyin X Yan Min M Xu Wenyue W Wassmer Samuel C SC Wang Jing J Chen Guangjie G Wang Zhaojun Z

Nature communications 20240129 1

Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myel ...[more]

PMID: 38286811

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Project description:Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). It is well established that citrullination of histones (e.g., CitH3) facilitates chromatin decondensation during NET formation (NETosis), particularly during calcium-induced NETosis that is independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation. However, the importance of other forms of histone modifications in NETosis has not been established. We considered that acetylation of histones would also facilitate NETosis. To test this hypothesis, we induced NOX-dependent NETosis in human neutrophils with phorbol myristate acetate or lipopolysaccharide (from Escherichia coli 0128), and NOX-independent NETosis with calcium ionophores A23187 or ionomycin (from Streptomycesconglobatus) in the presence or absence of two pan histone deacetylase inhibitors (HDACis), belinostat and panobinostat (within their half maximal inhibitory concentration (IC50) range). The presence of these inhibitors increased histone acetylation (e.g., AcH4) in neutrophils. Histone acetylation was sufficient to cause a significant increase (~20%) in NETosis in resting neutrophils above baseline values. When acetylation was promoted during NOX-dependent or -independent NETosis, the degree of NETosis additively increased (~15⁻30%). Reactive oxygen species (ROS) production is essential for baseline NETosis (mediated either by NOX or mitochondria); however, HDACis did not promote ROS production. The chromatin decondensation step requires promoter melting and transcriptional firing in both types of NETosis; consistent with this point, suppression of transcription prevented the NETosis induced by the acetylation of histones. Collectively, this study establishes that histone acetylation (e.g., AcH4) promotes NETosis at baseline, and when induced by both NOX-dependent or -independent pathway agonists, in human neutrophils. Therefore, we propose that acetylation of histone is a key component of NETosis.

Project description:RationaleAcute kidney injury (AKI) is a clinical syndrome associated with a multitude of conditions. Although renal replacement therapy (RRT) remains the cornerstone of treatment for advanced AKI, its implementation can potentially pose risks and may not be readily accessible across all healthcare settings and regions. Elevated lactate levels are implicated in sepsis-induced AKI; however, it remains unclear whether increased lactate directly induces AKI or elucidates the underlying mechanisms.MethodsFor human, the measurement of lactate in arterial blood gas is performed using the direct determination of L-lactate through an electrode oxidation method by a blood gas analyzer. For mice, enzyme-linked immunosorbent assay (ELISA) kits were employed to quantify the concentrations of lactate and AKI biomarkers in blood and cell supernatant. The mouse model of AKI was performed with a single intraperitoneal (i.p.) administration of lactate (30 mg/kg) and low-dose LPS (2 mg/kg) for 24 h. Proteomic analysis was conducted to identify lactylated proteins in kidney tissues. Techniques such as, immunoprecipitation, western blotting and immunofluorescence were used to evaluate the levels of HMGB1 lactylation, neutrophil extracellular traps (NETs)and to assess related molecular signaling pathways.Main resultsOur findings indicate that lactate serves as an independent predictor of AKI in patients with acute decompensated heart failure (ADHF). We observed that co-administration of lactate with low-dose lipopolysaccharide (LPS) resulted in lactate overproduction, which subsequently elevated serum levels of creatinine (Cre) and blood urea nitrogen (BUN). Furthermore, the combined application of lactate and low-dose LPS was shown to provoke HMGB1 lactylation within renal tissues. Notably, pretreatment with HMGB1 small interfering RNA (siRNA) effectively diminished lactate-mediated HMGB1 lactylation and alleviated the severity of AKI. Additionally, lactate accumulation was found to enhance the expression levels of NETs in the bloodstream, with circulating NETs levels positively correlating with HMGB1 lactylation. Importantly, pre-administration of HMGB1 inhibitors (glycyrrhizin) or lactate dehydrogenase A (LDH-A) inhibitors (oxamate) reversed the upregulation of NETs induced by lactate and low-dose LPS in both the blood and polymorphonuclear neutrophils (PMNs) cell supernatant, thereby ameliorating AKI associated with lactate accumulation.ConclusionsThese findings illuminate the role of lactate-mediated HMGB1 lactylation in inducing AKI in mice through the activation of the HMGB1-NETs signaling pathway.

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PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury.

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PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury.

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