Annexin A1 translocates to nucleus and promotes the expression of pro-inflammatory cytokines in a PKC-dependent manner after OGD/R

Abstract

Annexin A1 (ANXA1) is a protein known to have multiple roles in the regulation of inflammatory responses. In this study, we find that after oxygen glucose deprivation/reoxygenation (ODG/R) injury, activated PKC phosphorylated ANXA1 at the serine 27 residue (p27S-ANXA1), and promoted the translocation of p27S-ANXA1 to the nucleus of BV-2 microglial cells. This in turn induced BV-2 microglial cells to produce large amounts of pro-inflammatory cytokines. The phenomenon could be mimicked by either transfecting a mutant form of ANXA1 with its serine 27 residue converted to aspartic acid, S27D, or by using the PKC agonist, phorbol 12-myristate 13-acetate (PMA) in these microglial cells. In contrast, transfecting cells with an ANXA1 S27A mutant (serine 27 converted to alanine) or treating the cells with the PKC antagonist, GF103209X (GF) reversed this effet. Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines.

S100A11 protects against neuronal cell apoptosis induced by cerebral ischemia via inhibiting the nuclear translocation of annexin A1

“…In comparison, lipopolysaccharides 38 , glucocorticoids 15 , and hepatocyte growth factors induce ANXA1 membrane translocation. ANXA1 nuclear translocation was recently shown to be involved in neuronal apoptosis 5 , 6 , 10 and ANXA1 membrane translocation has been implicated in neuronal survival after OGD/R. According to the results from our current study, S100A11 overexpression promotes a direct interaction between S100A11 and ANXA1 after OGD/R.…”

“…This model was applied in the present study to simulate cerebral ischemia in vitro 7 – 9 . The factors influencing ANXA1 nuclear translocation have rarely been discussed 10 . Therefore, the critical factors and mechanisms underlying ANXA1 nuclear translocation after stroke are being urgently sought.…”

“…ANXA1 does not contain a classical nucleus localization signal, but our recent study revealed that the amino-acid residue sequence Arg 228 -Phe 237 (RSFPHLRRVF) of ANXA1 is crucial for the interaction of ANXA1 with importin β and functions as a unique nuclear translocation signal (NTS) 19 . ANXA1 accumulates in the nucleus through the association of this NTS with importin β and subsequently binds to p53, thus increasing p53 transcriptional activity, inducing the pro-apoptotic Bid gene expression, and activating the caspase-3 apoptosis pathway, eventually resulting in cell apoptosis after OGD/R 5 , 6 , 10 . Therefore, studies aiming to identify the factors that specifically block the nuclear translocation of ANXA1 may provide promising targeted strategies for the treatment of ischemic stroke.…”

Annexin-1 Mediates Microglial Activation and Migration via the CK2 Pathway during Oxygen–Glucose Deprivation/Reperfusion

“…ANXA1 had been found expressed in cultured neuron and microglia (including BV-2 microglia), and OGD/R treatment significantly increased the expression in these cells [17,22,23]. In present study we found that, in rat hippocampus ANXA1 was largely expressed in neurons and only rarely ANXA1 particles were observed in microglia, in contrast FPRs were richly expressed in microglia and only rarely in neurons.…”

Connections of annexin A1 and translocator protein-18 kDa on toll like receptor stimulated BV-2 cells

“…Furthermore conflicting results about ANXA1 actions on NF-κB translocation into nucleus have been described in different cell types. Constitutive augmented levels of ANXA1 on cancer cells induces NF-κB translocation [40], and we previously showed that the N-terminal peptide of ANXA1 (Ac-2-26), which binds to both FPR1 and FPR2, impaired the endotoxin-induced uveitis in rats, independently on inhibition of NF-κB translocation into nucleus of LPS stimulated ARPE-19 cells [41].…”