Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke

Abstract

Background: Efferocytosis of apoptotic neurons by macrophages is essential for the resolution of inflammation and for neuronal protection from secondary damage. It is known that alteration of the Sigma-1 receptor (Sig-1R) is involved in the pathological development of some neurological diseases, including ischemic stroke. The present study aimed to investigate whether and how Sig-1R regulates the phagocytic activity of macrophages/microglia and its significance in neuroprotection and neurological function in stroke. Methods: The roles of Sig-1R in the efferocytosis activity of microglia/macrophages using bone marrow-derived macrophages (BMDMs) or using Sig-1R knockout mice subjected to transient middle artery occlusion (tMCAO)-induced stroke were investigated. The molecular mechanism of Sig-1R in the regulation of efferocytosis was also explored. Adoptive transfer of Sig-1R intact macrophages to recipient Sig-1R knockout mice with tMCAO was developed to observe its effect on apoptotic neuron clearance and stroke outcomes. Results: Depletion of Sig-1R greatly impaired the phagocytic activity of macrophages/microglia, accordingly with worsened brain damage and neurological defects in Sig-1R knockout mice subjected to tMCAO. Adoptive transfer of Sig-1R intact bone marrow-derived macrophages (BMDMs) to Sig-1R knockout mice restored the clearance activity of dead/dying neurons, reduced infarct area and neuroinflammation, and improved long-term functional recovery after cerebral ischemia. Mechanistically, Sig-1R-mediated efferocytosis was dependent on Rac1 activation in macrophages, and a few key sites of Rac1 in its binding pocket responsible for the interaction with Sig-1R were identified. Conclusion: Our data provide the first evidence of the pivotal role of Sig-1R in macrophage/microgliamediated efferocytosis and elucidate a novel mechanism for the neuroprotection of Sig-1R in ischemic stroke.

Neutrophil-like pH-responsive pro-efferocytic nanoparticles improve neurological recovery by promoting erythrophagocytosis after intracerebral hemorrhage

“…However, most of the existing studies concentrate on the downstream events after ICH 10 , 76 - 78 . There were few researches about endogenous clearance of hematoma, which mainly focused on how to enhance interaction between microglia/macrophage and erythrocytes by regulating the associated signaling pathways, such as promoting the expression of phagocytic receptors or reducing phagocytosis-inhibiting signal 4 , 7 , 79 - 81 . The process by which phagocytes deal with phagocytic cargoes was often overlooked.…”

Donepezil-associated survival benefits among Alzheimer’s disease patients are retained but not enhanced during COVID-19 infections

“…These include regulating acute cellular stress, autophagy, and apoptosis 14,15 ; neuroplasticity, inflammation, and repair 28,29 ; and macrophage inflammatory cytokine production, polarization, and function. 30,31 Loss of sigma-1 activity also appears to increase age-related physical and neurologic pathology, 13 and sigma-1 receptor agonists are currently being explored as a therapeutic strategy to treat AD. 32 These wide-spread effects make it impossible to discount the possibility that donepezil mediates protection in part via sigma-1 receptor agonist activity.…”