Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon‐beta

Abstract

Apoptosis of autoaggressive T‐cells in the CNS is an effective, noninflammatory mechanism for the resolution of T‐cell infiltrates, contributing to clinical recovery in T‐cell‐mediated neuroinflammatory diseases. The clearance of apoptotic leukocytes by tissue‐specific phagocytes is critical in the resolution of the inflammatory infiltrate and leads to a profound downregulation of phagocyte immune functions. Adult human microglia from surgically removed normal brain tissue was used in a standardized, light‐microscopic in vitro phagocytosis assay of apoptotic autologous peripheral blood‐derived mononuclear cells (MNCs). Microglia from five different patients had a high capacity for the uptake of apoptotic MNCs in contrast to nonapoptotic target cells with the phagocytosis rate for nonapoptotic MNCs amounting to only 61.6% of the apoptotic MNCs. A newly described phosphatidylserine receptor, critical in the phagocytosis of apoptotic cells by macrophages, is also expressed at similar levels on human microglia. The effects of the therapeutically used immunomodulatory agent interferon‐beta (IFNβ) were investigated using Lewis rat microglia and apoptotic, encephalitogenic, myelin basic protein‐specific autologous T‐cells. Also, rat microglia had a high capacity to phagocytose apoptotic T‐cells specifically. IFNβ increased the phagocytosis of apoptotic T‐cells to 36.8% above the untreated controls. The enhanced phagocytic activity was selective for apoptotic T‐cells and was not mediated by increased IL‐10 secretion. Apoptotic inflammatory cells may be efficiently and rapidly removed by microglial cells in the autoimmune‐inflamed human CNS. The in vitro increase of phagocytosis by IFNβ merits further investigations whether this mechanism could also be therapeutically exploited. © 2003 Wiley‐Liss, Inc.

Neuroimmune Response in Ischemic Preconditioning

“…Other type 1 IFNs modulate the expression of nitric oxide and glutamate, which decreases the incidence of microglia-mediated neuronal death [96,97]. IRFs, downstream of IFN signaling, play a crucial role in the polarization of microglia and macrophages [98][99][100]. Furthermore, IFN-β enhances the ability of microglia to phagocytose apoptotic T cells, thus resulting in a modulation of the peripheral immune response [101].…”

Erythropoietin as an antiapoptotic, tissue-protective cytokine

“…The marked in vivo reduction of recruitment of microglia into the region of injury is likely explained by the reduced expression of cell surface markers of apoptosis, for example, phosphatidylserine. 41 It should be noted that this proinflammatory role of phosphatidylserine conflicts with other works showing that it stimulates phagocytosis but not inflammation -rather anti-inflammation (for instance: Chan et al, 42 De Simone et al 43 and Brouckaert et al 44 )).…”

Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death

“…Furthermore, the phagocytic removal of apoptotic leukocytes by microglia has been shown to contribute to the resolution of autoimmune processes (55). It is therefore conceivable that inhibition of phagocytosis (as a therapeutic measure) would block these beneficial processes.…”