Microglial Phagocytosis of Apoptotic Inflammatory T Cells Leads to Down-Regulation of Microglial Immune Activation

Abstract

Apoptotic cell death is an established mechanism to terminate an inflammatory response in rodent or human brains. Microglia, as the resident phagocyte, is a strong candidate for the clearance of apoptotic lymphocytes. Apoptosis was induced in cultured autologous thymocytes and in myelin basic protein (MBP)-specific, encephalitogenic T cells from Lewis rats by the addition of 0.1 μg/ml methylprednisolone. The amount of phagocytosis of apoptotic cells was assessed using an in vitro phagocytosis assay. Supernatants were collected to measure microglial cytokine secretion. The state of immune activation in microglia was investigated by a T cell proliferation assay and by flow cytometric analysis of microglial surface expression of immune molecules. Microglia ingested specifically apoptotic cells (apoptotic thymocytes as well as MBP-specific T cells) in contrast to nonapoptotic control cells (p < 0.0001). Subsequent secretion of the proinflammatory cytokines TNF-α and IL-12 was significantly decreased, while the secretion of IL-10 and TGF-β was not affected. Furthermore, ingestion of apoptotic cells led to increased microglial MHC class II expression without concomitant increase in MHC class I, costimulatory molecules, and ICAM expression. The Ag-specific activation of MBP-specific T cells in cocultures with microglia that had ingested apoptotic cells was significantly less than that of identical T cells that interacted with nonphagocytosing microglia. Together with negative results obtained in a trans-well system, this is in support of a cell contact-mediated effect. Microglia might play an important role in the clearance of apoptotic cells. The uptake of apoptotic cells by microglia is tolerogenic and results in a reduced proinflammatory cytokine production and a reduced activation of encephalitogenic T cells. This might help to restrict an autoimmune inflammation and minimize damage in the inflamed brain.

The neuron-astrocyte-microglia triad in CA3 after chronic cerebral hypoperfusion in the rat: Protective effect of dipyridamole

“…Several authors have indicated that microglial activation following neuronal injury represents mainly a protective mechanism that limits further neurodegeneration (Minghetti and Levi 1998;Streit et al 1999;Polazzi and Contestabile 2002). Indeed, it has been shown that phagocytosis of apoptotic cells by microglia decreases the production of pro-inflammatory cytokines, such as TNF-α and IL-12, without affecting the secretion of anti-inflammatory and potentially neuroprotective molecules, such as IL-10 and TGF-ßl (Magnus et al 2001). It has also been demonstrated that microglia releases molecules able to rescue neurons from apoptotic death and, in turn, diffusible signals from apoptotic neurons enhance the neuroprotective properties of microglia (Polazzi et al 2001).…”

Apolipoprotein E Modulates Clearance of Apoptotic Bodies In Vitro and In Vivo, Resulting in a Systemic Proinflammatory State in Apolipoprotein E-Deficient Mice

“…Not only is the clearance of such cellular debris an important function of tissue phagocytes, making it an appealing hypothesis to suggest that phagocyte number should be linked to the amount of debris awaiting clearance, but more recently a molecular mechanism to explain such a link has been uncovered. Huynh and coworkers (50) demonstrated that macrophages secrete the cytokine TGF-␤ upon taking up apoptotic bodies, at least in the lung and peritoneum, although a different mechanism seems to be operative in brain (51). Since TGF-␤ is a major anti-inflammatory cytokine acting to suppress monocyte recruitment into a range of tissues (52), this provides a mechanistic link between apoptotic clearance and macrophage numbers: if uptake of apoptotic bodies is impaired, then TGF-␤ secretion will be reduced and macrophage numbers will increase.…”

Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis

“…They remove damaged structures such as apoptotic cells and obsolete synaptic connections from the extracellular space (Kreutzberg, 1996). Whereas the uptake of foreign material leads to microglial activation to engage an immunological response, ingestion of apoptotic bodies is associated with an anti-inflammatory reaction (Magnus et al, 2001). By contrast, endogenous molecules derived from injured or necrotic cells serve as danger signals to microglia Lehnardt et al, 2008).…”