Increased susceptibility of annexin‐A1 null mice to nociceptive pain is indicative of a spinal antinociceptive action of annexin‐A1

Abstract

Background and purpose: Annexin-A1 (ANXA1), a glucocorticoid-regulated protein, mediates several of the antiinflammatory actions of the glucocorticoids. Previous studies demonstrated that ANXA1 is involved in pain modulation. The current study, using ANXA1 knockout mice (ANXA1 À/À ), is aimed at addressing the site and mechanism of the modulatory action of ANXA1 as well as possible involvement of ANXA1 in mediating the analgesic action of glucocorticoids. Experimental approach: The acetic acid-induced writhing response was performed in ANXA1À/À and wild-type (ANXA1 þ / þ ) mice with spinal and brain levels of prostaglandin E 2 (PGE 2 ) examined in both genotypes. The effect of the ANXA1 peptomimetic Ac2-26 as well as methylprednisolone on the writhing response and on spinal cord PGE 2 of ANXA1 þ / þ and ANXA1 À/À was compared. The expression of proteins involved in PGE 2 synthesis, cytosolic phospholipase A 2 (cPLA 2 ) and cyclooxygenases (COXs), in the spinal cord of ANXA1 þ / þ and ANXA1 À/À was also compared. Key results: ANXA1 À/À mice exhibited a significantly greater writhing response and increased spinal cord levels of PGE 2 compared with ANXA1 þ / þ mice. Ac2-26 produced analgesia and reduced spinal PGE 2 levels in ANXA1 þ / þ and ANXA1 À/À mice, whereas methylprednisolone reduced the writhing response and spinal PGE 2 levels in ANXA1mice. The expression of cPLA 2 , COX-1, COX-2 and COX-3 in spinal cord tissues was upregulated in ANXA1 À/À compared with ANXA1 þ / þ . Conclusions and implications: We conclude that ANXA1 protein modulates nociceptive processing at the spinal level, by reducing synthesis of PGE 2 by modulating cPLA 2 and/or COX activity. The analgesic activity of methylprednisolone is mediated by spinal ANXA1.

Annexin Peptide Ac2-26 Suppresses TNFα-Induced Inflammatory Responses via Inhibition of Rac1-Dependent NADPH Oxidase in Human Endothelial Cells

“…How Ac2-26 interferes with the activation of NADPH oxidase is not fully understood. Annexin-1 or Ac2-26 peptide has previously been shown to inhibit phospholipase A2 [49], [50] and phosopholipases are involved in the activation of NADPH oxidase in several cell types [14], [51]. We therefore propose that Ac2-26 may target phospholipase and this then interferes with NADPH oxidase assembly to reduce superoxide generation.…”

Annexin A1 modulates macula densa function by inhibiting cyclooxygenase 2

“…Further studies are required to elucidate the nature of these factors and their contribution to the regulation of ANXA1. The relationship between ANXA1 on COX-2 expression has also been extensively studied in ANXA1 knockout mice in which stimulation of COX-2 expression was found in some but not all tissues suggesting a cell-specific effect of ANXA1 on COX-2 expression (1,13,15). In cultured microglial cells, the NH 2 -terminal ANXA1 peptide AC2-26 caused a significant downregulation of COX-2 expression and PGE 2 synthesis.…”

Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

“…Consistent with this notion, AnxA1-deficient mice display inappropriate inflammatory responses in a number of disease models including experimental autoimmune encephalomyelitis (9), cerebral ischemia reperfusion (10), and nociception (11). In patients suffering from ulcerative colitis, AnxA1 expression at the site of tissue injury is upregulated during remission, suggesting a role in wound repair (12).…”