Neutrophils play a crucial role in the intertwined processes of thrombosis and inflammation. An altered neutrophil phenotype may contribute to inadequate resolution, which is known to be a major pathophysiological contributor of thromboinflammatory 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 the 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 the FPR2/ALX (a fundamental receptor involved in resolution) pathway. We found direct evidence that neutrophils with SCD phenotype play a key role in contributing to thromboinflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal–regulated kinases (ERK1/2) to enable resolution. We present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thromboinflammatory conditions such as SCD.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grants HL134959-01A1 (F.N.E.G.); grants HL098435, HL133497, and HL141155 and National Institute of General Medical Sciences grant GM12130 (A.W.O.); and grant HL142604 (R.P.); American Heart Association grant 19PRE34380751 (Z.A.-Y.); and Royal Society Wolfson Foundation grant RSWF\R3\183001 (F.N.E.G.).
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