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Role of Annexin A1 in NLRP3 Inflammasome Activation in Murine Neutrophils.

ABSTRACT: This study evaluated the role of endogenous and exogenous annexin A1 (AnxA1) in the activation of the NLRP3 inflammasome in isolated peritoneal neutrophils. C57BL/6 wild-type (WT) and AnxA1 knockout mice (AnxA1^-/-) received 0.3% carrageenan intraperitoneally and, after 3 h, the peritoneal exudate was collected. WT and AnxA1^-/- neutrophils were then stimulated with lipopolysaccharide, followed by the NLRP3 agonists nigericin or ATP. To determine the exogenous effect of AnxA1, the neutrophils were pretreated with the AnxA1-derived peptide Ac_2-26 followed by the NLRP3 agonists. Ac_2-26 administration reduced NLRP3-derived IL-1? production by WT neutrophils after nigericin and ATP stimulation. However, IL-1? release was impaired in AnxA1^-/- neutrophils stimulated by both agonists, and there was no further impairment in IL-1? release with Ac_2-26 treatment before stimulation. Despite this, ATP- and nigericin-stimulated AnxA1^-/- neutrophils had increased levels of cleaved caspase-1. The lipidomics of supernatants from nigericin-stimulated WT and AnxA1^-/- neutrophils showed potential lipid biomarkers of cell stress and activation, including specific sphingolipids and glycerophospholipids. AnxA1 peptidomimetic treatment also increased the concentration of phosphatidylserines and oxidized phosphocholines, which are lipid biomarkers related to the inflammatory resolution pathway. Together, our results indicate that exogenous AnxA1 negatively regulates NLRP3-derived IL-1? production by neutrophils, while endogenous AnxA1 is required for the activation of the NLRP3 machinery.

SUBMITTER: Sanches JM

PROVIDER: S-EPMC7827236 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Role of Annexin A1 in NLRP3 Inflammasome Activation in Murine Neutrophils.

Sanches José Marcos JM Correia-Silva Rebeca D RD Duarte Gustavo H B GHB Fernandes Anna Maria A P AMAP Sánchez-Vinces Salvador S Carvalho Patrícia O PO Oliani Sonia M SM Bortoluci Karina R KR Moreira Vanessa V Gil Cristiane D CD

Cells 20210111 1

This study evaluated the role of endogenous and exogenous annexin A1 (AnxA1) in the activation of the NLRP3 inflammasome in isolated peritoneal neutrophils. C57BL/6 wild-type (WT) and AnxA1 knockout mice (AnxA1<sup>-/-</sup>) received 0.3% carrageenan intraperitoneally and, after 3 h, the peritoneal exudate was collected. WT and AnxA1<sup>-/-</sup> neutrophils were then stimulated with lipopolysaccharide, followed by the NLRP3 agonists nigericin or ATP. To determine the exogenous effect of AnxA1 ...[more]

PMID: 33440601

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Project description:BackgroundNeospora caninum is an intracellular parasite that causes significant economic losses in cattle industry. Understanding the host resistance mechanisms in the innate immune response to neosporosis could facilitate the exploration of approaches for controlling N. caninum infection. The NLR inflammasome is a multiprotein platform in the cell cytoplasm and plays critical roles in the host response against microbes.MethodsNeospora caninum-infected wild-type (WT) macrophages and Nlrp3 -/- macrophages, and inhibitory approaches were used to investigate inflammasome activation and its role in N. caninum infection. Inflammasome RT Profiler PCR Arrays were used to identify the primary genes involved in N. caninum infection. The expression of the sensor protein NLRP3, processing of caspase-1, secretion of IL-1β and cell death were detected. Neospora caninum replication in macrophages was also assessed.ResultsMany NLR molecules participated in the recognition of N. caninum, especially the sensor protein NLRP3, and further study revealed that the NLRP3 distribution became punctate in the cell cytoplasm, which facilitated inflammasome activation. Inflammasome activation-mediated caspase-1 processing and IL-1β cleavage in response to N. caninum infection were observed and were correlated with the time of infection and number of infecting parasites. LDH-related cell death was also observed, and this death was regarded as beneficial for the clearance of N. caninum. Treatment of N. caninum-infected macrophages with caspase-1, pan-caspase and NLRP3 inhibitors led to the impaired release of active IL-1β and a failure to restrict parasite replication. And Neospora caninum infected peritoneal macrophages from Nlrp3-deficient mice displayed greatly decreased release of active IL-1β and the failure of caspase-1 cleavage.ConclusionsThe NLRP3 inflammasome can be activated in N. caninum-infected macrophages, and plays a protective role in the host response to control N. caninum.

Dataset Information

Role of Annexin A1 in NLRP3 Inflammasome Activation in Murine Neutrophils.

Publications

Role of Annexin A1 in NLRP3 Inflammasome Activation in Murine Neutrophils.

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