The role of annexin A1 in the modulation of the NLRP3 inflammasome

Abstract

Annexins are well-known Ca 2+ phospholipid-binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti-inflammatory and proresolving properties through its binding to the formyl-peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)-1b release in response to activators of the nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL-1b release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL-1b, NLRP3 and caspase-1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co-localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti-inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2-independent manner.Bone marrow-derived macrophages (BMDMs) were obtained as previously described. 31 Briefly, bone marrow cells were collected from femurs of wild-type (WT), AnxA1 À/À and FPR2/3 À/À mice and differentiated for 7 days in RPMI 1640 supplemented with 20% of fetal bovine serum (FBS) and 30% L929 conditioned medium.

Annexin A1 Regulates NLRP3 Inflammasome Activation and Modifies Lipid Release Profile in Isolated Peritoneal Macrophages

“…Despite our findings, recent analyses show that bone-marrow-derived AnxA1 -/macrophages produced significantly lower secretion of IL-1β when activated with monosodium urate (MSU) crystals and ATP, but not NLRC4 or AIM2 activators (Legionella pneumophila or poly(dA:dT)) [28]. Notably, during the setting of MSU crystal-induced inflammation, the peak of the neutrophil influx was greater, and the resolution was slower in AnxA1 -/mice than in WT animals [29].…”

Rationale for the Use of Radiation-Activated Mesenchymal Stromal/Stem Cells in Acute Respiratory Distress Syndrome

“…Moreover, new studies indicating an intracellular function of ANXA1 have now been published. In effect, using AnxA1 knockout mice, it has been noted that ANSA1 is essential for IL-1β release both in vivo as in vitro [ 65 ]. Furthermore, we know that ANXA1 colocalize and exactly connect with NLRP3, suggesting the activity of ANXA1 in inflammasome initiation is independent of its anti-inflammatory role via FPR2 [ 65 ].…”

“…In effect, using AnxA1 knockout mice, it has been noted that ANSA1 is essential for IL-1β release both in vivo as in vitro [ 65 ]. Furthermore, we know that ANXA1 colocalize and exactly connect with NLRP3, suggesting the activity of ANXA1 in inflammasome initiation is independent of its anti-inflammatory role via FPR2 [ 65 ]. These mechanisms, which could be of major importance in the resolution of lung inflammation and in septic shock through cytokine storm control, deserve more research.…”

The hidden role of NLRP3 inflammasome in diabesity-related COVID-19 exacerbations: lessons for drug repurposing

“…The main actors of this process consist of specialized proresolving mediators (SPMs), whose list is constantly updated, including annexin A1 (AnxA1), formyl-peptide receptor 2 (FPR2) and lipoxin A 4 (LXA 4 ) (Brancaleone et al, 2013;Dufton et al, 2010;Norling, Dalli, Flower, Serhan & Perretti, 2012;Serhan, Chiang & Dalli, 2015). Very recently, AnxA1 has been reported to be involved in the regulation of NLRP3 inflammasome function (Galvao et al, 2020), independently from the binding to its cognate receptor FPR2 (Galvao et al, 2020). Indeed, lower levels of AnxA1 are associated to an increased activation of NLRP3, thus raising IL-1β releasing (Kelley, Jeltema, Duan & He, 2019).…”