Apoptotic cells promote their own clearance and immune tolerance through activation of LXR

By Noelia A-González, S. Bensinger, Cynthia Hong, Susana Beceiro, Michelle N. Bradley, N. Zelcer, José Déniz, Cristina Ramírez, Mercedes Díaz, G. Gallardo and 8 more. Immunity, 2009

668 citations recorded by the source corpus.

Summary Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We demonstrate here that LXR signaling is important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activates LXR and thereby induces the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR null macrophages exhibit a selective defect in phagocytosis of apoptotic cells and an aberrant pro-inflammatory response to them. As a consequence of these defects, mice lacking LXRs manifest a breakdown in self-tolerance and develop autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorates disease progression in mouse models of Lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/da4da4c41ebdc65bb6c96f2869e34c28d3e4c428

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In Immunology

Citations in the corpus

The Cellular Biology of Macrophages in Atherosclerosis (2011, positive): “, 2007); LXR activators, which increase expression of MerTK, secretion of the efferocytosis effector apolipoprotein E, and ABCA1/G1-mediated efflux of toxic sterols (A-Gonzalez et al., 2009; Yancey et al., 2010; Yvan-Charvet et al., 2010b); and PPARd activators, which enhance efferocytosis in vitro ”
Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells (2010, background): “The recent findings that PPARδ and LXRs positively regulate the expression of TYRO3, AXL and MER (also known as TAM) receptors, which are a family of receptor tyrosine kinases that have important anti-inflammatory roles in several cell types including macrophage”
Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells (2011, background): “Phagocytes that have engulfed apoptotic cells instigate tolerogenic pathways designed to prevent an unwanted autoimmune response (29).”
The spleen in local and systemic regulation of immunity (2013, background): “Apoptotic cell engulfment activates LXRa and LXRb and induces the expression of the receptor tyrosine kinase Mer, which is required for phagocytosis (A-Gonzalez et al., 2009).”
Efficient clearance of early apoptotic cells by human macrophages requires “M2c” polarization and MerTK induction (2012, background): “MerTK is expressed on phagocytes following exposure to ACs and subsequent LXR receptor activation (5).”