Necrotic Cell Sensor Clec4e Promotes a Pro-Atherogenic Macrophage Phenotype Through Activation of the Unfolded Protein Response
Background—Atherosclerotic lesion expansion is characterized by the development of a lipid rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. Clec4e receptor recognizes the cord factor of M. Tuberculosis, but also senses molecular patterns released by necrotic cells, and drives inflammation.
Methods—We hypothesized that activation of Clec4e signaling by necrosis is causally involved in atherogenesis. We addressed the impact of Clec4e activation on macrophage functions in vitro, and on the development of atherosclerosis using low-density lipoprotein receptor deficient (Ldlr-/-) mice in vivo.
Results—We show that Clec4e is expressed within human and mouse atherosclerotic lesions, and is activated by necrotic lesion extracts. Clec4e signaling in macrophages inhibits cholesterol efflux and induces a Syk-mediated endoplasmic reticulum (ER) stress response, leading to the induction of pro-inflammatory mediators and growth factors. Chop and Ire1a deficiencies significantly limit Clec4e-dependent effects, whereas Atf3 deficiency aggravates Clec4e-mediated inflammation and alteration of cholesterol efflux. Repopulation of Ldlr-/- mice with Clec4e-/- bone marrow reduces lipid accumulation, ER-stress, macrophage inflammation and proliferation within the developing arterial lesions, and significantly limits atherosclerosis.
Conclusions—Our results identify a non-redundant role for Clec4e in coordinating major biological pathways involved in atherosclerosis, and suggest that it may play similar roles in other chronic inflammatory diseases.
- Received March 23, 2016.
- Revision received July 15, 2016.
- Accepted August 5, 2016.