Annexin A1: A Central Player in the Anti-Inflammatory and Neuroprotective Role of Microglia

Abstract

The brain microenvironment is continuously monitored by microglia with the detection of apoptotic cells or pathogens being rapidly followed by their phagocytosis to prevent inflammatory responses. The protein annexin A1 (ANXA1) is key to the phagocytosis of apoptotic leukocytes during peripheral inflammatory resolution, but the pathophysiological significance of its expression in the CNS that is restricted almost exclusively to microglia is unclear. In this study, we test the hypothesis that ANXA1 is important in the microglial clearance of apoptotic neurons in both noninflammatory and inflammatory conditions. We have identified ANXA1 to be sparingly expressed in microglia of normally aged human brains and to be more strongly expressed in Alzheimer's disease. Using an in vitro model comprising microglial and neuronal cell lines, as well as primary microglia from wild-type and ANXA1 null mice, we have identified two distinct roles for microglial ANXA1: 1) controlling the noninflammatory phagocytosis of apoptotic neurons and 2) promoting resolution of inflammatory microglial activation. In particular, we showed that microglial-derived ANXA1 targets apoptotic neurons, serving as both an “eat me” signal and a bridge between phosphatidylserine on the dying cell and formyl peptide receptor 2 on the phagocytosing microglia. Moreover, inflammatory activation of microglia impairs their ability to discriminate between apoptotic and nonapoptotic cells, an ability restored by exogenous ANXA1. We thus show that ANXA1 is fundamental for brain homeostasis, and we suggest that ANXA1 and its peptidomimetics can be novel therapeutic targets in neuroinflammation.

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

“…To further investigate the mechanism whereby recombinant ANXA1 could rescue the permeability deficit seen in AnxA1 −/− mice or in AS clones, we analyzed the role of FPR2, which we have previously shown to mediate the actions of ANXA1 in different cellular contexts (14,17,18). By using flow cytometry, we confirmed the presence of FPR2 on the surface of hCMEC/D3 cells (Fig.…”

“…From each paraffin block, 8-μm sections were cut and used for immunohistochemistry as described later. Human plasma samples from patients with MS and healthy donors were used to measure ANXA1 content by ELISA as reported previously (18).…”

Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death

“…Furthermore, knockout of the putative PS receptor in mice prevents developmental neuronal loss leading to pathologically enlarged brains (48), and microglia are known to mediate the loss of neurons in the developing mouse cerebellum and hippocampus (49,50). These findings are suggestive of microglia or microglial phagocytosis contributing to neuronal death in mammals, and using immortalized cell lines, a recent study has reported the phagocytosis of The Journal of Immunology"normal" neurons by LPS-or amyloid-activated microglia (51). However, whether the inhibition of phagocytosis can prevent neuronal death has so far not been tested.…”

Annexin-A1 Regulates TLR-Mediated IFN-β Production through an Interaction with TANK-Binding Kinase 1

“…The FPR family of proteins are G protein-coupled, pattern recognition receptors. Therefore, exogenous ANXA1 can act on FPRs to dampen inflammatory monocyte activation (22) and resolve inflammation (23,24).…”