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

Abstract

Annexin A1 (AnxA1) is a potent anti-inflammatory protein that downregulates proinflammatory cytokine release. This study evaluated the role of AnxA1 in the regulation of NLRP3 inflammasome activation and lipid release by starch-elicited murine peritoneal macrophages. C57bl/6 wild-type (WT) and AnxA1-null (AnxA1 -/-) mice received an intraperitoneal injection of 1.5% starch solution for macrophage recruitment. NLRP3 was activated by priming cells with lipopolysaccharide for 3 h, followed by nigericin (1 h) or ATP (30 min) incubation. As expected, nigericin and ATP administration decreased elicited peritoneal macrophage viability and induced IL-1β release, more pronounced in the AnxA1 -/cells than in the control peritoneal macrophages. In addition, nigericin-activated AnxA1 -/macrophages showed increased levels of NLRP3, while points of co-localization of the AnxA1 protein and NLRP3 inflammasome were detected in WT cells, as demonstrated by ultrastructural analysis. The lipidomic analysis showed a pronounced release of prostaglandins in nigericin-stimulated WT peritoneal macrophages, while ceramides were detected in AnxA1 -/cell supernatants. Different eicosanoid profiles were detected for both genotypes, and our results suggest that endogenous AnxA1 regulates the NLRP3-derived IL-1β and lipid mediator release in macrophages.

Communications Between Bone Marrow Macrophages and Bone Cells in Bone Remodeling

“…Proteomic studies have shown that macrophage-derived EVs contain a large number of alarmins (one of endogenous molecules) ( Figure 3 ). Annexins can stimulate bone resorption (Li et al, 2005 ), improve the phagocytic efficiency of macrophage (Stukes et al, 2016 ), which is related to Multiple myeloma (MM) (D'Souza et al, 2012 ) and play an auxiliary role of macrophages in infected tissues (Silva et al, 2019 ; McArthur et al, 2020 ; Sanches et al, 2020 ). Galectins mainly affect the differentiation of bone marrow stromal cells (Andersen et al, 2003 ), osteoblast, osteoclast (Shimura et al, 2005 ; Nakajima et al, 2014 ; Simon et al, 2017 ; Iacobini et al, 2018 ) and the osteogenesis of mesenchymal stem cells (Weilner et al, 2016 ).…”

Targeting AnxA1/Formyl Peptide Receptor 2 Pathway Affords Protection against Pathological Thrombo-Inflammation

“…Phospholipase (e.g., calcium-dependent cytosolic phospholipase A 2 (“cPLA 2 ”)) activity releases arachidonic acid (“AA”) from phospholipids in the outer nuclear membrane. Once released, the free fatty acid can be metabolized via enzymatic pathways including the (COX) and lipoxygenase (LOX) pathways, generating 2-series prostaglandins (PGs) and thromboxanes (Txs) (COX pathway) or 4-series leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) (LOX pathway) [ 63 ]. Transcellular production of lipoxins and leukotrienes ensues when contact is made between e.g., neutrophils and platelets.…”

“…More recently, Sanches et al showed that macrophages lacking AnxA1 have increased AA metabolism and eicosanoid production. This lack of AnxA1 favours LPS “over-priming” and exacerbated NLR Family Pyrin Domain Containing 3 (“NLRP3”) activation, demonstrating an important role for AnxA1 in inflammasome activation [ 63 ]. Other studies have also shown AnxA1 to exert its effects via the FPR2/ALX/p38 mitogen-activated protein kinase (“MAPK”)/COX-2 pathway in an experimental model of intracerebral haemorrhage, although other MAPKs may also be involved [ 65 ].…”

Special Issue “Recent Developments in Annexin Biology”

“…Their review article describes how AnxA2, which in the homeostatic state sustains anti-inflammatory functions during acute as well as chronic inflammatory states, contributes to disease states when this homeostasis is disrupted. Sanches et al [ 9 ] extend the roles of annexins in inflammation by exploring the involvement of AnxA1 in the inhibition of the release of inflammatory mediators by macrophages. They show that the release of these mediators is increased, leading to greater inflammasome activation in macrophages lacking AnxA1, which causes reduced viability.…”