Innate recognition of apoptotic cells: novel apoptotic cell-associated molecular patterns revealed by crossreactivity of anti-LPS antibodies

Tennant, I; Pound, John D.; Marr, Lisa; Willems, Jorine J.L.P.; Петрова, С. А.; Ford, Catriona A.; Paterson, Mary; Devitt, Andrew; Gregory, Christopher D.

doi:10.1038/cdd.2012.165

Cited by 12 publications

(9 citation statements)

References 42 publications

(40 reference statements)

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“…This may help explain why TLR-4 -/- macrophages take up AC more efficiently than TLR4 +/+ macrophages [49]. Previous studies have addressed TLR involvement in AC removal as PRRs are proposed to bind ACAMPs - ligands that have recently been revealed on the surface of AC [27]. However TLR4 is involved in phagosome maturation rather than AC-tethering [49].…”

Section: Discussionmentioning

confidence: 99%

“…Recently a novel strategy to identify ACAMPs has been used successfully, through the use of anti-LPS mAbs. However, whilst this epitope colocalised with annexin V- and C1q-binding sires on AC, it did not appear to interact preferentially with CD14 [27]. …”

Section: Discussionmentioning

confidence: 99%

“…CD14) mediating AC clearance [25,26]. In support of this, LPS-like structures have recently been revealed on cells undergoing apoptosis [27]. …”

Section: Introductionmentioning

confidence: 94%

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The N-Terminus of CD14 Acts to Bind Apoptotic Cells and Confers Rapid-Tethering Capabilities on Non-Myeloid Cells

et al. 2013

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Cell death and removal of cell corpses in a timely manner is a key event in both physiological and pathological situations including tissue homeostasis and the resolution of inflammation. Phagocytic clearance of cells dying by apoptosis is a complex sequential process comprising attraction, recognition, tethering, signalling and ultimately phagocytosis and degradation of cell corpses. A wide range of molecules acting as apoptotic cell-associated ligands, phagocyte-associated receptors or soluble bridging molecules have been implicated within this process. The role of myeloid cell CD14 in mediating apoptotic cell interactions with macrophages has long been known though key molecules and residues involved have not been defined. Here we sought to further dissect the function of CD14 in apoptotic cell clearance. A novel panel of THP-1 cell-derived phagocytes was employed to demonstrate that CD14 mediates effective apoptotic cell interactions with macrophages in the absence of detectable TLR4 whilst binding and responsiveness to LPS requires TLR4. Using a targeted series of CD14 point mutants expressed in non-myeloid cells we reveal CD14 residue 11 as key in the binding of apoptotic cells whilst other residues are reported as key for LPS binding. Importantly we note that expression of CD14 in non-myeloid cells confers the ability to bind rapidly to apoptotic cells. Analysis of a panel of epithelial cells reveals that a number naturally express CD14 and that this is competent to mediate apoptotic cell clearance. Taken together these data suggest that CD14 relies on residue 11 for apoptotic cell tethering and it may be an important tethering molecule on so called ‘non-professional’ phagocytes thus contributing to apoptotic cell clearance in a non-myeloid setting. Furthermore these data establish CD14 as a rapid-acting tethering molecule, expressed in monocytes, which may thus confer responsiveness of circulating monocytes to apoptotic cell derived material.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The N-Terminus of CD14 Acts to Bind Apoptotic Cells and Confers Rapid-Tethering Capabilities on Non-Myeloid Cells

et al. 2013

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“…However, even in the absence of infection or lactation, CD14 and other genes involved in innate immunity are highly induced during regression of the mammary gland after weaning (Stein et al, 2004 ). The role of CD14 during this period of glandular remodeling may be the recognition and disposal of apoptotic cells (Heidenreich, 1999 ; Devitt et al, 2004 ; Tennant et al, 2013 ). We speculate that vitamin D induction of soluble CD14 in mammary tissue inhibits activation of tissue resident macrophages, suppressing inflammation which is known to drive cancer development and progression(McMahon et al, 2011 ; Simpson and Brown, 2013 ).…”

Section: Vitamin D Pathway Expression In Normal Mammary Cells and Brementioning

confidence: 99%

The impact of vitamin D in breast cancer: genomics, pathways, metabolism

et al. 2014

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Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts with its ligand 1α,25(OH)2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH)2D3 and the VDR in regulation of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (i.e., epithelial, adipose, fibroblast, endothelial, immune) of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH)2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer.

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“… 86 , 87 Recently anti-PAMP antibodies have been used to probe apoptotic cells to identify ACAMPs. 88 Scavenger receptors are a group of PRRs with identified roles in apoptotic cell recognition, with CD14 (the prototypic PRR) having a well-established role in responses to LPS through its functional association with signalling partner toll-like receptor 4 (TLR4). 89 However, CD14 also mediates tethering of apoptotic cells to phagocytes, 84 , 90 though there has currently been no noted involvement of TLR4 in CD14-mediated binding of AC.…”

Section: Recognition and Tethering—‘eat Me’ Versus ‘Don’t Eat Me’mentioning

confidence: 99%

Current Understanding of the Mechanisms for Clearance of Apoptotic Cells—A Fine Balance

Hawkins

Devitt

2013

J�Cell Death

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Apoptosis is an important cell death mechanism by which multicellular organisms remove unwanted cells. It culminates in a rapid, controlled removal of cell corpses by neighboring or recruited viable cells. Whilst many of the molecular mechanisms that mediate corpse clearance are components of the innate immune system, clearance of apoptotic cells is an anti-inflammatory process. Control of cell death is dependent on competing pro-apoptotic and anti-apoptotic signals. Evidence now suggests a similar balance of competing signals is central to the effective removal of cells, through so called ‘eat me’ and ‘don’t eat me’ signals. Competing signals are also important for the controlled recruitment of phagocytes to sites of cell death. Consequently recruitment of phagocytes to and from sites of cell death can underlie the resolution or inappropriate propagation of cell death and inflammation. This article highlights our understanding of mechanisms mediating clearance of dying cells and discusses those mechanisms controlling phagocyte migration and how inappropriate control may promote important pathologies.

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Innate recognition of apoptotic cells: novel apoptotic cell-associated molecular patterns revealed by crossreactivity of anti-LPS antibodies

Cited by 12 publications

References 42 publications

The N-Terminus of CD14 Acts to Bind Apoptotic Cells and Confers Rapid-Tethering Capabilities on Non-Myeloid Cells

The N-Terminus of CD14 Acts to Bind Apoptotic Cells and Confers Rapid-Tethering Capabilities on Non-Myeloid Cells

The impact of vitamin D in breast cancer: genomics, pathways, metabolism

Current Understanding of the Mechanisms for Clearance of Apoptotic Cells—A Fine Balance

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