Abstract
BackgroundEarly brain injury (EBI) has been thought to be a key factor affecting the prognosis of subarachnoid hemorrhage (SAH). Many pathologies are involved in EBI, with inflammation and neuronal death being crucial to this process. Resolvin D1 (RvD1) has shown superior anti-inflammatory properties by interacting with lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) in various diseases. However, it remains not well described about its role in the central nervous system (CNS). Thus, the goal of the present study was to elucidate the potential functions of the RvD1-ALX/FPR2 interaction in the brain after SAH.MethodsWe used an in vivo model of endovascular perforation and an in vitro model of hemoglobin (Hb) exposure as SAH models in the current study. RvD1 was used at a concentration of 25 nM in our experiments. Western blotting, quantitative polymerase chain reaction (qPCR), immunofluorescence, and other chemical-based assays were performed to assess the cellular localizations and time course fluctuations in ALX/FPR2 expression, evaluate the effects of RvD1 on Hb-induced primary microglial activation and neuronal damage, and confirm the role of ALX/FPR2 in the function of RvD1.ResultsALX/FPR2 was expressed on both microglia and neurons, but not astrocytes. RvD1 exerted a good inhibitory effect in the microglial pro-inflammatory response induced by Hb, possibly by regulating the IRAK1/TRAF6/NF-κB or MAPK signaling pathways. RvD1 could also potentially attenuate Hb-induced neuronal oxidative damage and apoptosis. Finally, the mRNA expression of IRAK1/TRAF6 in microglia and GPx1/bcl-xL in neurons was reversed by the ALX/FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4), indicating that ALX/FPR2 could mediate the neuroprotective effects of RvD1.ConclusionsThe results of the present study indicated that the RvD1-ALX/FPR2 interaction could potentially play dual roles in the CNS, as inhibiting Hb promoted microglial pro-inflammatory polarization and ameliorating Hb induced neuronal oxidant damage and death. These results shed light on a good therapeutic target (ALX/FPR2) and a potential effective drug (RvD1) for the treatment of SAH and other inflammation-associated brain diseases.
Highlights
Subarachnoid hemorrhage (SAH) is a serious hemorrhagic disease of the central nervous system (CNS)
ALX/FPR2 is elevated after subarachnoid hemorrhage (SAH) and primarily expresses in neurons and microglia, rather than astrocytes The location of ALX/FPR2 expression has remained controversial
Different results were obtained from in vitro experiments (Fig. 1c), where ALX/FPR2 exhibited the highest expression in primary neuron, followed by primary microglia, while primary astrocytes did not exhibit ALX/FPR2 expression
Summary
Subarachnoid hemorrhage (SAH) is a serious hemorrhagic disease of the central nervous system (CNS). RvD1 has been shown to exert good regulatory effects on inflammation, evidenced by its ability to limit the recruitment or infiltration of neutrophils [7, 8], to inhibit the production of pro-inflammatory factors [9, 10], and to promote neutrophil apoptosis and their efferocytosis by macrophages [11] These functions may be mediated by ALX/FPR2 [12], a type of G-protein-coupled receptors (GPCR). Resolvin D1 (RvD1) has shown superior anti-inflammatory properties by interacting with lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) in various diseases. It remains not well described about its role in the central nervous system (CNS). The goal of the present study was to elucidate the potential functions of the RvD1-ALX/FPR2 interaction in the brain after SAH
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