Glucocorticoids Promote Nonphlogistic Phagocytosis of Apoptotic Leukocytes

Abstract

Phagocyte recognition, uptake, and nonphlogistic degradation of neutrophils and other leukocytes undergoing apoptosis promote the resolution of inflammation. This study assessed the effects of anti-inflammatory glucocorticoids on this leukocyte clearance mechanism. Pretreatment of “semimature” 5-day human monocyte-derived macrophages (Mφ) for 24 h with methylprednisolone, dexamethasone, and hydrocortisone, but not the nonglucocorticoid steroids aldosterone, estradiol, and progesterone, potentiated phagocytosis of apoptotic neutrophils. These effects were specific in that the potentiated phagocytosis of apoptotic neutrophils was completely blocked by the glucocorticoid receptor antagonist RU38486, and glucocorticoids did not promote 5-day Mφ ingestion of opsonized erythrocytes. Similar glucocorticoid-mediated potentiation was observed with 5-day Mφ uptake of alternative apoptotic “targets” (eosinophils and Jurkat T cells) and in uptake of apoptotic neutrophils by alternative phagocytes (human glomerular mesangial cells and murine Mφ elicited into the peritoneum or derived from bone marrow). Importantly, methylprednisolone-mediated enhancement of the uptake of apoptotic neutrophils did not trigger the release of the chemokines IL-8 and monocyte chemoattractant protein-1. Furthermore, longer-term potentiation by methylprednisolone was observed in maturing human monocyte-derived Mφ, with greater increases in 5-day Mφ uptake of apoptotic cells being observed the earlier glucocorticoids were added during monocyte maturation into Mφ. We conclude that potentiation of nonphlogistic clearance of apoptotic leukocytes by phagocytes is a hitherto unrecognized property of glucocorticoids that has potential implications for therapies aimed at promoting the resolution of inflammatory diseases.

Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS

“…Efferocytosis describes the ability of a macrophage to clear apoptotic cells. The ability of glucocorticoids to upregulate AM efferocytosis is dependent on HSD-1 expression ( 17 , 18 ). Glucocorticoids increase macrophage efferocytosis partly by upregulating expression of the efferocytosis receptor Mer ( 37 , 38 ) and downregulating expression of the inhibitory receptor Signal Regulatory Protein-α (SIRPα) ( 39 ) on the surface of macrophages.…”

“…Efferocytosis is a process associated with the suppression of inflammatory responses and promotion of tissue repair ( 15 , 16 ). Glucocorticoids have the ability to upregulate macrophage efferocytosis; but this capacity is dependent on HSD-1 expression ( 17 , 18 ). Murine studies have shown that macrophage HSD-1 deficiency is associated with impaired efferocytosis of apoptotic neutrophils in a model of peritonitis ( 18 ).…”

Lip synechiae: A sequelae of carbamazepine‐induced erythema multiforme. A case report and review of current perspectives and controversies

“…31,34 Although systemic steroids are commonly used, the level of evidence for their use is low and inconsistent. 5,28,31 Glucocorticoids have pro-resolution inflammatory properties thus attenuate the acute inflammatory process 35 through the various cellular and chemical mechanisms including the down-regulation of cytokine gene expression such as of TNF-α 36 and promotion of nonphlogistic phagocytosis of apoptotic leucocytes. 35 A few case series have shown benefit with reduction in morbidity when treated with systemic steroids 37,38 whereas others have reported increased morbidity with longer healing time.…”

“…5,28,31 Glucocorticoids have pro-resolution inflammatory properties thus attenuate the acute inflammatory process 35 through the various cellular and chemical mechanisms including the down-regulation of cytokine gene expression such as of TNF-α 36 and promotion of nonphlogistic phagocytosis of apoptotic leucocytes. 35 A few case series have shown benefit with reduction in morbidity when treated with systemic steroids 37,38 whereas others have reported increased morbidity with longer healing time. 39 Baillis and Maize 7 reported a case with successful use of adalimumab, a recombinant IgG1 monoclonal antibody with specificity for human TNF-α in the treatment of recalcitrant EM.…”

All-trans retinoic acid and dexamethasone regulate phagocytosis-related gene expression and enhance dead cell uptake in C2C12 myoblast cells

“…Various efferocytosis receptor combinations are produced by phagocytes, in different organs, but they all come and work together at the phagocytic synapse to mediate tethering and generate enough engulfment signals after macrophages connect to the apoptotic cells 9 . Previously, the glucocorticoid receptor (GR) and retinoic acid receptors (RARs) nuclear receptors were shown to increase efferocytosis in macrophages by promoting the transcription of key phagocytic machinery genes 10 – 12 .…”