Serum amyloid A opposes lipoxin A₄to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) will soon be the third most common cause of death globally. Despite smoking cessation, neutrophilic mucosal inflammation persistently damages the airways and fails to protect from recurrent infections. This maladaptive and excess inflammation is also refractory to glucocorticosteroids (GC). Here, we identify serum amyloid A (SAA) as a candidate mediator of GC refractory inflammation in COPD. Extrahepatic SAA was detected locally in COPD bronchoalveolar lavage fluid, which correlated with IL-8 and neutrophil elastase, consistent with neutrophil recruitment and activation. Immunohistochemistry detected SAA was in close proximity to airway epithelium, and in vitro SAA triggered release of IL-8 and other proinflammatory mediators by airway epithelial cells in an ALX/FPR2 (formyl peptide receptor 2) receptor-dependent manner. Lipoxin A 4 (LXA 4 ) can also interact with ALX/FPR2 receptors and lead to allosteric inhibition of SAA-initiated epithelial responses (pA 2 13 nM). During acute exacerbation, peripheral blood SAA levels increased dramatically and were disproportionately increased relative to LXA 4 . Human lung macrophages (CD68 + ) colocalized with SAA and GCs markedly increased SAA in vitro (THP-1, pEC 50 43 nM). To determine its direct actions, SAA was administered into murine lung, leading to induction of CXC chemokine ligand 1/2 and a neutrophilic response that was inhibited by 15-epi-LXA 4 but not dexamethasone. Taken together, these findings identify SAA as a therapeutic target for inhibition and implicate SAA as a mediator of GC-resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors. resolution | leukocyte activation | G protein-coupled receptor | innate immunity

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

“…The anti-inflammatory and proresolving actions of these novel peptides are in line with the actions displayed by the potent antiinflammatory and proresolving mediators LXA 4 and AT-LXA 4 that are both FPR2/ALX agonists (14,39). Notably, it has recently been demonstrated in that serum amyloid A, another FPR2/ALX may blunt the anti-inflammatory actions of LXA 4 , which, in turn, may mediate glucocorticoid refractory lung inflammation in patients with chronic obstructive pulmonary disease (39).…”

“…Notably, it has recently been demonstrated in that serum amyloid A, another FPR2/ALX may blunt the anti-inflammatory actions of LXA 4 , which, in turn, may mediate glucocorticoid refractory lung inflammation in patients with chronic obstructive pulmonary disease (39). These findings further underscore the complexity of ligand-receptor interactions mediated by FPR2/ALX that may lead to the activation of specific signaling pathways, ultimately resulting in functionally distinct cellular responses.…”

Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses

“…It is noteworthy that, whereas LXA 4 did not affect the ALX conformational change promoted by AnxA1, SAA did reduce this response, thus providing a molecular explanation for the antagonistic properties of SAA and AnxA1 (25).…”

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

“…LXA 4 is a potent stimulus for macrophage phagocytosis (32). Additionally, LXA 4 inhibits neutrophil transepithelial migration (33) and airway epithelial proinflammatory mediator expression in an ALX/FPR2-dependent manner (33,34). LXA 4 also displays mucosal protection by stimulating ZO-1 expression and transepithelial electrical resistance in human airway epithelial cells (35).…”