Beyond apoptosis in lupus

Colonna, Lucrezia; Lood, Christian; Elkon, Keith B.

doi:10.1097/bor.0000000000000083

Cited by 61 publications

(44 citation statements)

References 71 publications

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“…In contrast, C1s inhibition does not cause significant accumulation nor affects the immunosuppressive properties of early apoptotic cells. This likely occurs because, under physiological conditions, the redundancy in both opsonins and phagocytic receptors enables swift and efficient uptake and clearance of dying cells [57,58]. …”

Section: Discussionmentioning

confidence: 99%

“…Lupus patients have defects in AC clearance [59,60], which lead to secondary necrosis (late AC) with exposure of intracellular self-antigens and spillage of inflammatory mediators, thus predisposing to autoimmunity [57,58,61,62]. Our observations are consistent with previous studies showing that late apoptotic/secondary necrotic Annexin V+PI+ cells, rather than early apoptotic Annexin V+PI− cells, activate the classical complement pathway and show increased serum-dependence for their phagocytic clearance [11,41,42,44].…”

Section: Discussionmentioning

confidence: 99%

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Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

Colonna

Parry²,

Panicker³

et al. 2016

Clinical Immunology

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Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

Colonna

Parry²,

Panicker³

et al. 2016

Clinical Immunology

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“…Defective expression of engulfment receptors has been reported in patients with SLE (reviewed in (15, 44)). Deficiencies in the early components of complement, C1q and C4, are strongly associated with the development of SLE (reviewed in (45, 46)).…”

Section: Visualizing Clearance Of Cells Undergoing Apoptosis In Situmentioning

confidence: 99%

The many ways tissue phagocytes respond to dying cells

Blander

2017

Immunological Reviews

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Summary Apoptosis is an important component of normal tissue physiology, and the prompt removal of apoptotic cells is equally essential to avoid the undesirable consequences of their accumulation and disintegration. Professional phagocytes are highly specialized for engulfing apoptotic cells. The recent ability to track cells that have undergone apoptosis in situ has revealed a division of labor among the tissue resident phagocytes that sample them. Macrophages are uniquely programmed to process internalized apoptotic cell-derived fatty acids, cholesterol and nucleotides, as a reflection of their dominant role in clearing the bulk of apoptotic cells. Dendritic cells carry apoptotic cells to lymph nodes where they signal the emergence and expansion of highly suppressive regulatory CD4 T cells. A broad suppression of inflammation is executed through distinct phagocyte-specific mechanisms. A clever induction of negative regulatory nodes is notable in dendritic cells serving to simultaneously shut down multiple pathways of inflammation. Several of the genes and pathways modulated in phagocytes in response to apoptotic cells have been linked to chronic inflammatory and autoimmune diseases such as atherosclerosis, inflammatory bowel disease and systemic lupus erythematosus. Our collective understanding of old and new phagocyte functions after apoptotic cell phagocytosis demonstrates the enormity of ways to mediate immune suppression and enforce tissue homeostasis.

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“…This evidence includes the fact that the dominant autoantigens targeted in SLE are largely nuclear components that are exposed on apoptotic blebs (1,2). Moreover, the body of evidence suggests that increased cell death and defective clearance are primary drivers of SLE development and progression (3).…”

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confidence: 99%

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

Ravishankar

Liu

Shinde

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

127

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Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic celldriven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.immunometabolism | stress | tolerance | autoimmunity | apoptosis M ultiple lines of evidence suggest that apoptotic cells are a major source of autoantigens in the autoimmune disease systemic lupus erythematosus (SLE). This evidence includes the fact that the dominant autoantigens targeted in SLE are largely nuclear components that are exposed on apoptotic blebs (1, 2). Moreover, the body of evidence suggests that increased cell death and defective clearance are primary drivers of SLE development and progression (3).In homeostatic conditions, apoptotic cells drive suppressive innate and adaptive tolerogenic immune responses that protect against initiation of inflammatory autoimmunity. Macrophages (MΦ) are key drivers of the early innate response to apoptotic cells (4, 5), and recent work has shown that tissue-resident MΦs are responsible for initial IL-10 production, promoting regulatory adaptive immunity to apoptotic cell antigens and prevention of inflammatory autoimmunity (4, 6, 7).On a molecular level, the mechanisms driving the initial tolerogenic response of myeloid cells to apoptotic material in vivo are poorly defined, although studies suggest a direct role for inhibitory signaling via the MAPK pathway (8), and a recent report indicated that responses to cytoplasmic DNA may be a key mechanism of tolerance to self (9). Likewise, we have reported that apoptoti...

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Beyond apoptosis in lupus

Cited by 61 publications

References 71 publications

Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

The many ways tissue phagocytes respond to dying cells

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

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