Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity

Abstract

Among the distinct molecular signatures present in the mitochondrion is the tetra-acylated anionic phospholipid cardiolipin, a lipid also present in primordial, single-cell bacterial ancestors of mitochondria and multiple bacterial species today. Cardiolipin is normally localized to the inner mitochondrial membrane; however, when cardiolipin becomes externalized to the surface of dysregulated mitochondria, it promotes inflammasome activation and stimulates the elimination of damaged or nonfunctional mitochondria by mitophagy. Given the immunogenicity of mitochondrial and bacterial membranes that are released during sterile and pathogen-induced trauma, we hypothesized that cardiolipins might function as “eat me” signals for professional phagocytes. In experiments with macrophage cell lines and primary macrophages, we found that membranes with mitochondrial or bacterial cardiolipins on their surface were engulfed through phagocytosis, which depended on the scavenger receptor CD36. Distinct from this process, the copresentation of cardiolipin with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide dampened TLR4-stimulated production of cytokines. These data suggest that externalized, extracellular cardiolipins play a dual role in host-host and host-pathogen interactions by promoting phagocytosis and attenuating inflammatory immune responses.

The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia

“…We recently reported that concomitant exposure of cells to cardiolipin and lipopolysaccharide (LPS) in vitro inhibits the production of pro-inflammatory cytokines such as TNF-α by the cells22. However, these studies did not address the impact of cardiolipin in vivo on already established inflammation when cardiolipin levels increase in the extracellular milieu (Fig.…”

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

“…33,34 Finally, when released into the extracellular space, CLs on the surface of mitochondria or mitochondrial fragments, again mostly in their oxidized form, 35 can act as pro-phagocytotic 'eat me' signals via CD36 scavenger receptor and/or as suppressors of cytokine production potentially leading to immunoparalysis. 36 All these findings add to an emerging paradigm, namely that the myriad of different cellular lipid species, and in particular CL, have not just a supportive structural role, but are very actively involved in regulatory and signaling functions. 19,[37][38][39][40][41] …”

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

“…44 Beyond PtdSer, some other surface membrane moieties act as tolerogenic 'eat me' signals in a context-dependent manner (although the exact compositional balance of these with PtdSer is still debatable). These include externalized cardiolipin, 45 oxidized low-density lipoproteins, annexin-A1, thrombospondin, complement C1q and changes in membrane glycosylation status or charges (Figure 1). 6,15,46 Interestingly, in the context of chemotherapy-induced ICD, secretion of annexin-A1 by dying cancer cells followed by its binding to the formyl peptide receptor 1 on DCs, was found to facilitate recruitment of tumour-infiltrating DCs in close vicinity to the dying cancer cells and the formation of dead corpse/DC conjugates, resulting in immunogenic phagocytosis.…”