Nur77-Induced AICD in Macrophage
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Nur77-Induced AICD in Macrophage
PCD (Programmed Cell Death), often referred to as Apoptosis, is a genetically regulated, self-destructive cellular process found in metazoans. It eliminates individual cells when they are no longer needed in development, tissue remodeling, or immune regulation, as well as in various diseases. In immune cells, Apoptosis is a key phenomenon in AICD (Activation-Induced Cell Death) (Ref.1). Macrophages are specialized phagocytes responsible for ingesting and digesting senescent, dead, and damaged cells in many tissues as well as microorganisms. These are regarded as very important players in innate immunity because of their nonselective response to almost all infectious microorganisms. Because Macrophages play such a crucial role in immunity as well as in remodeling tissues, the life span of activated Macrophages is important in physiological and pathological processes. Although activated Macrophages are crucial for host defense, they are also dangerous as they can cause extensive tissue damage and inflammation if uncontrolled. In this regard, the cell death i.e., AICD of activated Macrophages could be a mechanism to control the level of inflammation (Ref.2).

Bacterial endotoxin, LPS (Lipopolysaccharide) is a complex glycolipid found in the outer membrane of all Gram-negative bacteria and is believed to play a crucial role in Gram-negative bacteria-induced cellular responses. Generally, LPS activates Macrophages and renders these cells to be more resistant to Apoptosis. In contrast, LPS can induce macrophage death in the presence of the pan-Caspase inhibitors, which generally prevent Apoptosis in many different types of cells including T-Cells and B-Cells. In this regard, the death program of Macrophages appears to be unique compared with other immune cells. Co-stimulation of Macrophages with LPS and the pan-Caspase inhibitor zVAD (Benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) results in death of activated Macrophages (Ref.3). Macrophage death induced by LPS and zVAD in combination is independent of the known proapoptotic Caspases. Signaling through TLRs (Toll-Like Receptors): TLR2 and TLR4 are required for macrophage death in this system. The orphan nuclear receptor Nur77 has a crucial role in macrophage AICD. Involvement of Nur77 in the macrophage death is well-documented from the fact that, cell death is reduced significantly in Nur77-deficient Macrophages (Ref. 2).

A dual signaling pathway leads to the induction of Nur77 expression by Macrophages that are destined to undergo AICD. Activation of the ERK (Extracellular Signal-Regulated Kinase) pathway, which is downstream of TLR signalling, and activity of the MEF2 (Myocyte-Specific Enhancer Binding Factor-2), which is upregulated by zVAD, are both required for the induction of Nur77 transcription and the subsequent macrophage cell death. The NAP, Ets, and Sp1 sites in the Nur77 promoter are regulated by TLR2 and TLR4 signaling and that MEF2 sites in the Nur77 promoter are regulated by zVAD. MEF2 transcription factors are constitutively expressed and degraded in Macrophages, and zVAD increases MEF2 transcription factor activity by preventing the proteolytic cleavage and degradation of MEF2 proteins. The integration of MEF2 activity with other transcription factors downstream of the ERK pathway on the Nur77 promoter is essential for Nur77 induction and cell death. ERK activation in activated Macrophages involves Ras, Raf, and MEKs (MAPK/ERK Kinases) (Ref.1&4).

Macrophage death has many different causes. Phagocytosis of infectious microorganisms by Macrophages is a part of the host response to infection. Infectious microbial pathogens can be killed by Macrophages, and their components are strong stimuli of macrophage activation. Activation of Macrophages can lead to their own death if they are exposed to viruses, or cytokines, such as IFN-Gamma (Interferon-Gamma) and IFN-Alpha (Interferon-Alpha). Activation of Macrophages by priming with IFN-Gamma is required for Macrophages to eliminate highly resistant microorganisms. Although activated Macrophages are crucial for host defense, they are also dangerous because they can cause extensive local damage if uncontrolled. AICD of activated Macrophages could be a crucial mechanism to control the level of Inflammation (Ref.4&5).