However, it is important to note th

However, it is important to note that while internalization of apoptotic cells can modulate the activity of multiple NRs, we presently do not know the cellular source or precise molecular nature of the NR-modulating ligands relevant to efferocytosis.In addition to promoting phagocytosis, NRs are involved in the regulation of macrophage inflammation during efferocytosis (119). For example, treatment of LXRα/β-deficient macrophages with apoptotic cells does not induce TGFβ and IL-10 production nor suppress IL-1β and IL-12 production like their WT counterparts (121). Similarly, macrophages lacking PPARδ fail to produce IL-10 and produce more TNF and IL-12 than WT macrophages when cultured with apoptotic cells (120). Also, macrophages from mice lacking PPARγ and RXRα are refractory to the immunosuppressive effects of apoptotic cells in vitro (122). More recently, the nuclear receptor Nr4a1 was found to be rapidly upregulated in macrophages cultured with apoptotic cells, and Nr4a1-deficient macrophages cultured with apoptotic cells showed enhanced NFkB activation and IL-12 production compared to WT macrophages (44, 123). Interestingly, Nr4a1 upregulation by apoptotic cells can occur via adenosine activation of the A2a receptor, suggesting regulation of this NR could be stimulated by nucleotide find-me signals as well as via phagosomal signaling. (44, 124).