Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

Li, Hao; Fu, Yang–Xin; Wu, Qi; Zhou, Yong; Crossman, David K.; Yang, PingAr; Li, Jun; Luo, Bao; Morel, Laurence; Kabarowski, Janusz H.; Yagita, Hideo; Ware, Carl F.; Hsu, Hui Chen; Mountz, John D.

doi:10.1172/jci81059

Cited by 55 publications

(69 citation statements)

References 62 publications

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“…found that an increase in pDCs is paralleled by a decrease in MZMs in the perifollicular region of the spleen (12). Remarkably, analysis of the distribution of MZMs and pDCs in the spleens of patients with SLE showed a similar pattern.…”

Section: Type I Ifns: Dictators Of Defective Ac Clearancementioning

confidence: 69%

“…Specifically, compared with healthy controls, patients with SLE exhibited a decrease in MZMs and an accumulation of pDCs in the spleen. Interestingly, IFNAR deficiency in BXD2 mice restored MZM numbers and prevented pDC aggregation in the spleen, suggesting (17,18), and that the activation of this signaling cascade is important for MZM homeostasis in the MZ as well as for clearance of ACs by MZMs (12). Moreover, MKL1-deficent mice displayed a decrease in MZMs and developed a spontaneous lupus-like disease, elegantly confirming the importance of the mLT/LTβR pathway and associated MKL1 expression in preventing lupus.…”

Section: Type I Ifns: Dictators Of Defective Ac Clearancementioning

confidence: 73%

“…While the role of ACs in promoting type I IFN overproduction in SLE is well documented, the effect of excess IFN on the clearance of ACs has remained uninvestigated. In this issue, Li and colleagues use a combination of genetic mouse models to demonstrate a novel role for type I IFNs in defective MZM-mediated clearance of ACs in SLE (12).…”

Section: Type I Ifns In Slementioning

confidence: 99%

“…Specifically, the authors demonstrated that the interaction between lymphotoxin β recepthat IFNAR signaling may promote lupus by dissipating phagocytic MZMs in the spleen (12). However, at this stage, the possibility that reduced MZM numbers in the spleens of patients with SLE are a consequence of different therapies cannot be excluded.…”

Section: Type I Ifns: Dictators Of Defective Ac Clearancementioning

confidence: 99%

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The many faces of type I interferon in systemic lupus erythematosus

Mauri¹,

Menon²

2015

J. Clin. Invest.

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C o m m e n t a r y 2 5 6 2 jci.org Volume 125 Number 7July 2015 The many faces of type I interferon in systemic lupus erythematosus Claudia Mauri and Madhvi MenonCentre for Rheumatology, Division of Medicine, University College London, London, United Kingdom. Systemic lupus erythematosus: a heterogeneous diseaseSystemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse clinical presentations that can affect multiple organ systems (1). The multiplicity of symptoms and pathologies are a result of the heterogeneous immunological abnormalities that contribute to disease pathogenesis. While the precise etiology of SLE is unknown, it is hypothesized to be a combination of genetic and environmental factors (1). The onset of clinical symptoms and subsequent diagnosis of SLE occur long after the initiation of disease, making it difficult to identify the causative factor(s). Defective apoptotic cell clearance by marginal zone macrophagesAn abnormal response to autoantigens is considered an important driving force in the development of human SLE (2) and is thought to be due to a defect in clearance of apoptotic cells (ACs), resulting in increased exposure of lymphocytes to internal cellular antigens (3). Lupus-associated autoantigens, including nucleosomal DNA and small nuclear ribonucleoproteins, have been identified on the blebs of ACs (3). The lack of AC clearance has been shown to be pivotal in the production of anti-nuclear antibodies (ANAs) against these antigens, and the presence of circulating ANAs is a diagnostic criterion for lupus. Immune complexes formed by autoantibodies and self-antigens accumulate in multiple organs, cause tissue damage, and promote a systemic inflammatory response (4). Although it is widely accepted that ACs contribute to SLE pathogenesis, the mechanisms responsible for the defective clearance of ACs remain poorly understood. Recently, it has become apparent that, in addition to B cells, several other cells of the immune system are defective in patients with SLE. These include cells of the innate immune system, such as macrophages and monocytes, which contribute to impaired phagocytosis and defective AC clearance (5). In particular, marginal zone macrophages (MZMs) surrounding the splenic follicles have been reported to play a crucial role in the efficient clearance of ACs and in the induction of tolerance to AC autoantigens (AC-Ags) (6). MZM dysfunction results in a loss of tolerance to self-antigens and a decrease in AC clearance (7). Type I IFNs in SLE

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Section: Type I Ifns: Dictators Of Defective Ac Clearancementioning

confidence: 69%

Section: Type I Ifns: Dictators Of Defective Ac Clearancementioning

confidence: 73%

Section: Type I Ifns In Slementioning

confidence: 99%

Section: Type I Ifns: Dictators Of Defective Ac Clearancementioning

confidence: 99%

See 2 more Smart Citations

The many faces of type I interferon in systemic lupus erythematosus

Mauri¹,

Menon²

2015

J. Clin. Invest.

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“…PPARγ agonists also exert anti-inflammatory and immunomodulatory effects, and the beneficial impacts of rosiglitazone were reported for the amelioration of the autoantibody production, renal disease, and atherosclerosis in MRL-lpr mice depending on the induction of adiponectin [1] and also in NZBWF1 mice [2]. SLE is associated with increased circulating apoptotic autoantigens and increased type I interferon (IFN) signaling which simulate the production of autoantibody including anti-dsDNA antibodies [3]. Genetic depletion of PPARδ decreased the expression of opsonins such as C1qb and Mertk, which was resulted in the impairment of clearance for apoptotic cells and autoimmune kidney disease resembling lupus nephritis in human [4].…”

Section: Systemic Lupus Erythematosus (Sle) Is An Inflammatory Autoimmentioning

confidence: 99%

LXR, PPAR<i>γ</i>, and PPAR<i>δ</i> Agonists Are Not Sufficient to Demonstrate Therapeutic Potential against Mouse Model of Systemic Lupus Erythematosus

Tatebe¹,

Watanabe²,

Zeggar³

et al. 2017

OJRA

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Aim: We aimed to investigate whether the agonists for liver X receptor (LXR) ameliorate lupus-like phenotypes in mice mediated by the clearance of apoptotic cells, and compare with peroxisome proliferator-activated receptor (PPAR) γ plus PPARδ agonists, which also facilitate the clearance of apoptotic cells and exert anti-inflammatory effects in systemic lupus erythematosus (SLE). Methods: We investigated the efficacy of LXR agonist (GW3965) or dual treatment of PPARγ (pioglitazone) and PPARδ (GW0742) agonists in SLE animal models, female MRL/MpJ-Fas/J mice and BALB/cAJcl mice treated with pristane. The data were analyzed with one-way analysis of variance and Tukey's honestly significant difference tests. Results: The treatment with LXR or PPARγ/δ agonists did not significantly alter the swelling of lymph nodes, ds-DNA production, albuminuria, histological score of glomerular lesions, and mRNA expression of target genes including Abca1, C1qa, Icam1, Mertk and Tnf. Conclusion: LXR or PPARγ/δ agonists targeting the impaired clearance for apoptosis cells may not be efficient in the remission induction therapy in SLE.

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Host Genetics But Not Commensal Microbiota Determines the Initial Development of Systemic Autoimmune Disease in BXD2 Mice

Hong

Alduraibi

Ponder

et al. 2022

Arthritis & Rheumatology

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Objective To determine the extent to which the gut microbiome influences systemic autoimmunity in a mouse model of lupus. Methods We generated germ‐free (GF) lupus‐prone BXD2 mice, which under normal conditions develop spontaneous germinal centers (GCs) and high titers of serum autoantibodies. GF status was confirmed by gut bacterial culture. The autoimmune phenotypes of 6‐ and 12‐month‐old gnotobiotic GF BXD2 mice and specific pathogen–free (SPF) BXD2 mice were compared. Serum levels of autoantibodies were measured by enzyme‐linked immunosorbent assay. Histologic sections of the mouse kidney and joints were evaluated. Flow cytometry was used to analyze GCs and age‐associated B cells. CD4+ T cells were analyzed for PD‐1+ICOS+ activated T cells, T follicular regulatory (Tfr) cells (Foxp3+CD25+ PD‐1+CXCR5+), and PD‐1+ICOS+ T cells expressing interleukin‐17A (IL‐17A) or interferon‐γ (IFNγ) after stimulation with phorbol myristate acetate (PMA)/ionomycin. Results In 6‐month‐old mice, GF status did not affect splenomegaly, GC B cells, age‐associated B cells, or serum autoantibody levels, except for IgG antihistone. GF BXD2 mice exhibited a significantly higher percentage of Tfr cells compared to their SPF counterparts (P < 0.05). At 12 months of age, however, GF BXD2 mice had significantly diminished IgG autoantibody levels and a lower percentage of GC B cells and age‐associated B cells (P < 0.05). Following stimulation with PMA/ionomycin, PD‐1+ICOS+ CD4+ T cells expressed significantly lower IL‐17A, but not IFNγ, levels in GF BXD2 mice compared to SPF BXD2 mice (P < 0.01). SPF BXD2 mice and GF BXD2 mice developed equivalent renal and joint disease with no significant differences in severity. Conclusion Our results suggest a model in which genetics plays a dominant role in determining the initial development of autoimmunity. In contrast, gut microbiomes may regulate the persistence of certain aspects of systemic autoimmunity.

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Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

Cited by 55 publications

References 62 publications

The many faces of type I interferon in systemic lupus erythematosus

The many faces of type I interferon in systemic lupus erythematosus

LXR, PPAR<i>γ</i>, and PPAR<i>δ</i> Agonists Are Not Sufficient to Demonstrate Therapeutic Potential against Mouse Model of Systemic Lupus Erythematosus

Host Genetics But Not Commensal Microbiota Determines the Initial Development of Systemic Autoimmune Disease in BXD2 Mice

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Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

Cited by 55 publications

References 62 publications

The many faces of type I interferon in systemic lupus erythematosus

The many faces of type I interferon in systemic lupus erythematosus

LXR, PPAR&lt;i&gt;γ&lt;/i&gt;, and PPAR&lt;i&gt;δ&lt;/i&gt; Agonists Are Not Sufficient to Demonstrate Therapeutic Potential against Mouse Model of Systemic Lupus Erythematosus

Host Genetics But Not Commensal Microbiota Determines the Initial Development of Systemic Autoimmune Disease in BXD2 Mice

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LXR, PPAR<i>γ</i>, and PPAR<i>δ</i> Agonists Are Not Sufficient to Demonstrate Therapeutic Potential against Mouse Model of Systemic Lupus Erythematosus