Targeting the AnxA1/Fpr2/ALX pathway regulates neutrophil function, promoting thromboinflammation resolution in sickle cell disease

Abstract

Neutrophils plays a crucial role in the intertwined processes of thrombosis and inflammation. Altered neutrophil phenotype may contribute to inadequate resolution which is known to be a major pathophysiological contributor of thrombo-inflammatory conditions such as Sickle Cell Disease (SCD). The endogenous protein Annexin A1 (AnxA1) facilitates inflammation resolution via Formyl Peptide Receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting neutrophil dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26 ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of FPR2/ALX (a fundamental receptor involved in resolution) pathway. We demonstrated direct evidence that neutrophils with SCD phenotype play a key role in contributing to thrombo-inflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2) to enable resolution. Herein, we present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thrombo-inflammatory conditions such as SCD.

Neutrophil and remnant clearance in immunity and inflammation

“…Macrophages derived from AnxA1-null mice exhibited a defect in efferocytic potential [97]. Further study demonstrated AnxA1Ac2-26 drives pro-NETotic to proapoptotic phenotype in neutrophils thereby inducing a non-inflammatory form of cell death [96]. In accordance, lipoxin A4 (LXA 4 ) exploits the N-formyl peptide receptor 2 (FPR2) for the efferocytosis and diminishes the release of pro-inflammatory cytokines leading to the resolution of inflammation.…”

“…Mice lacking MFG-E8 resulted in increased Tunnel-positive cells in the lungs and anti-NETs antibodies suggesting an aberrant clearance process [95]. A recent study exploited lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) pathway to promote the resolution of thrombosis in patients with sickle cell disease [96]. Pro-resolving, annexin A1 and its mimetic AnxA1Ac2-26 increase neutrophil apoptosis and also facilitate phagocytic uptake through ALX/FPR2 pathway [97].…”

The impact of thrombo‐inflammation on the cerebral microcirculation

“…53 Our work (Ansari et al) will further highlight the importance of pathological neutrophil function and hampered resolution biology in SCD cerebral phenotype and how exogenous Annexin A1 mimetic peptide Ac2-26 can mitigate neutrophil-dependent thromboinflammatory responses and attenuate thrombosis in SCD. 70…”

Neutrophils and Platelets: Immune Soldiers Fighting Together in Stroke Pathophysiology

“…Neutrophils and platelets are key players in ischemic brain injury and its resolution [ 4 , 5 , 6 , 7 ]. Resolution is the physiological ability of the body to achieve homeostasis after infection or inflammation.…”

“…Acute cerebral ischemia induces a strong immune response resulting in recruitment of several subsets of leukocytes (mainly neutrophils), activation of platelets, and coagulation cascade and upregulation of cell adhesion molecules and cytokines [ 10 ]. Neutrophils and platelets are known for their ability to produce proinflammatory/prothrombotic mediators, thereby forming an important link between inflammation and thrombosis, a phenomenon referred to as “thromboinflammation” [ 4 , 11 , 12 ]. The concept of thromboinflammation in stroke pathophysiology has gained considerable attention and traction in the last decade [ 4 , 12 ].…”