The balance between cell death and cell survival is crucial for tissue homeostasis in multicellular organisms (Green, 2003
). Unwanted cells are usually eliminated by apoptosis, a programmed cellular suicide conserved from worms to mammals that culminates in recognition and ingestion of dying cells by phagocytes (Henson and Hume, 2006
; Ravichandran and Lorenz, 2007
). In contrast to other types of phagocytosis, such as bacterial or necrotic cell uptake, scavenging of apoptotic cells is immunologically silent (Lauber et al., 2004
). Efficient disposal of apoptotic corpses prevents uncontrolled release of intracellular contents and is important for immunological self-tolerance (Ravichandran and Lorenz, 2007
). Intracellular pathways that link the engulfment of apoptotic corpses and suppression of inflammation are incompletely characterized. We have shown here that the nuclear receptor LXR is important for both apoptotic cell clearance and suppression of the inflammatory response during their phagocytosis.
Prior work has shown LXR to be critical for macrophage cholesterol homeostasis (Castrillo and Tontonoz, 2004
; Repa and Mangelsdorf, 2002
). In response to lipoprotein uptake via scavenger receptors, macrophages activate an LXR-dependent pathway for cholesterol efflux. Unexpectedly, we found that phagocytosis of apoptotic cells also activates LXR, likely through the accumulation of membrane-derived cholesterol. LXR in turn activates transcription of Mer, thereby providing positive feedback to promote further clearance, as well as genes such as Abca1
to promote efflux of the excess cholesterol (Tontonoz and Mangelsdorf, 2003
). At the same time, LXR activation in response to apoptotic cells also suppresses the production of inflammatory mediators. Since cholesterol is not a component of pathogens such as bacteria, activation of LXR by apoptotic cell-derived cholesterol provides a mechanism to suppress inflammatory responses in some phagocytic pathways but permit them in others.
Collectively, our data provide a new physiological context in which to view the dual activation and transrepression functions of LXR. Activation of genes such as Abca1 fits well with the established function of this receptor in cholesterol homeostasis. The biological significance of LXR’s transrepressive function, however, has been less clear. Is the ability to repress inflammatory gene expression related to cholesterol metabolism, or is this an activity that evolved for a completely separate purpose? We have shown that the process of apoptotic cell clearance integrates both direct gene activation and transrepression and that, at least in this context, inhibition of inflammatory gene expression is intimately linked to metabolism of apoptotic cell lipids. These results illustrate that the activation and transrepression functions of LXR are both important for normal immune homeostasis.
Considerable data support the idea that defective clearance of apoptotic cells leads to autoimmunity (Henson and Hume, 2006
; Savill et al., 2002
; Vaux and Flavell, 2000
). For example, SLE patients exhibit an impaired ability to clear apoptotic cells, and corpses and DNA remnants are found in their serum (Herrmann et al., 1998
; Kalden, 1997
; Licht et al., 2004
). In mice lacking Mfge8, Mer or C1q, lupus-like manifestations have been linked to inefficient removal of apoptotic cells (Botto et al., 1998
; Cohen et al., 2002
; Hanayama et al., 2004
). We have shown that loss of LXR-dependent regulation of Mer and inappropriate activation of inflammatory signaling during phagocytosis leads to the development of autoimmune disease. Interestingly, Mer
-/- and Lxr
αβ-/- mice share a number of striking similarities, including exacerbated inflammatory responses and increased susceptibility to both autoimmunity and atherosclerosis (Ait-Oufella et al., 2008
; Camenisch et al., 1999
; Cohen et al., 2002
; Joseph et al., 2003
; Thorp et al., 2008
). At the same time, the fact that autoimmune disease is more severe in Lxr
αβ-/- compared to Mer
-/- mice suggests that more than one LXR-dependent pathway may be involved. We have recently shown that loss of LXRβ leads to increased lymphocyte proliferation (Bensinger et al., 2008
). It is likely that the phenotype of Lxr
αβ-/- mice reflects both the action of LXRα and LXRβ in antigen presenting cells as well as the autonomous effect of LXRβ in lymphocytes. It is also possible that loss of regulation of ABCA1, ApoE (Grainger et al., 2004
; Hamon et al., 2000
) and other targets contributes to the autoimmune phenotype of LXR null mice. The question of whether defects in the LXR signaling pathway may contribute to the development of human autoimmune disease remains to be investigated.
Finally, we have shown that pharmacological LXR activation has beneficial effects on the progression of autoimmune disease in mouse models of lupus-like disease. A previous study reported that a different LXR agonist slowed the development of disease in an experimental autoimmune encephalomyelitis model, although the underlying mechanism was not addressed (Hindinger et al., 2006
). Our studies indicate that LXR activation may compensate for the macrophage phagocytic defect characteristic of lupus-like autoimmunity. In addition, it is likely that the ability of LXRs to directly suppress inflammation and inhibit lymphocyte proliferation also contribute to the therapeutic effects of LXR agonists in these disease models. Further studies will be required to explore the possibility that LXR agonists may have utility in the therapy of human autoimmune disease.