The inflammasome and lupus

Kahlenberg, J. Michelle; Kaplan, Mariana J.

doi:10.1097/bor.0000000000000088

Cited by 127 publications

(52 citation statements)

References 68 publications

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“…Thus, cholesterol accumulation in ABC DKO DCs leads to inflammasome activation, increased secretion of IL-1β and IL-18 and skewing of T-cells towards a T h 1 phenotype. Interestingly, IL-18 levels are markedly elevated in human SLE, and inflammasome activation contributes to lupus glomerulonephritis in mice (Kahlenberg and Kaplan, 2014; Kahlenberg et al, 2014; Tucci et al, 2008), suggesting a role for inflammasome activation in the autoimmune phenotype of DC-ABC DKO mice.…”

Section: Resultsmentioning

confidence: 99%

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

et al. 2017

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Summary Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with increased cardiovascular disease and reduced plasma high-density lipoproteins (HDL) levels. HDL mediates cholesterol efflux from immune cells via the ATP Binding Cassette Transporters A1 and G1 (ABCA1/G1). The significance of impaired cholesterol efflux pathways in autoimmunity is unknown. We observed that Abca1/g1 deficient mice develop enlarged lymph nodes (LNs) and glomerulonephritis suggestive of SLE. This lupus-like phenotype was recapitulated in mice with knockouts of Abca1/g1 in dendritic cells (DCs) but not in macrophages or T-cells. DC-Abca1/g1 deficiency increased LN and splenic CD11b+ DCs, which displayed cholesterol accumulation and inflammasome activation, increased cell surface levels of the GM-CSF receptor, and enhanced inflammatory cytokine secretion. Consequently, DC-Abca1/g1 deficiency enhanced T-cell activation, Th1 and Th17-cell polarization. NLRP3 inflammasome deficiency diminished the enlarged LNs and enhanced Th1-cell polarization. These findings identify an essential role of DC cholesterol efflux pathways in maintaining immune tolerance.

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Section: Resultsmentioning

confidence: 99%

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

et al. 2017

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“…The role of components of the innate immune response in the pathogenesis of systemic autoimmune diseases, such as lupus, has been increasingly recognized [15,16]. Lupus is characterized by activation of plasmacytoid dendritic cells, a robust type-I interferon expression signature, and hyper-responsiveness of PBMCs to type-I interferon [17,18].…”

Section: Discussionmentioning

confidence: 99%

Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils

Coit

Yalavarthi

Ognenovski

et al. 2015

Journal of Autoimmunity

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161

115

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Recent evidence suggests that neutrophils play an important role in the pathogenesis of lupus. The goal of this study was to characterize the epigenetic architecture, by studying the DNA methylome, of neutrophils and low density granulocytes (LDGs) in lupus patients. We studied 15 lupus patients and 15 healthy age, sex, and ethnicity matched controls. Genome-wide DNA methylation was assessed using the Illumina HumanMethylation 450 BeadChip array, which includes over 485,000 methylation sites across the entire genome. Bisulfite DNA sequencing was used to validate the array results. Statistical and bioinformatic analysis was performed to identify and characterize differentially methylated loci and genes. We identified 293 differentially methylated CG sites in neutrophils between lupus patients and controls. The majority (68%) of differentially methylated CG sites were hypomethylated in lupus neutrophils compared to controls, suggesting overall hypomethylation. We found a robust and consistent demethylation of interferon signature genes in lupus neutrophils, and similar demethylation in the same genes in autologous LDGs. Indeed, the DNA methylome in lupus neutrophils and LDGs was almost identical, suggesting similar chromatin architecture in the two granulocyte subsets. A notable exception was the hypomethylation of a CG site in the promoter region of the cytoskeleton-regulating gene RAC1 in LDGs. Our findings demonstrate a pattern of robust demethylation of interferon signature genes in lupus patients supporting a pathogenic role for neutrophils in lupus. We suggest a model whereby DNA from lupus neutrophils and LDGs externalized by NETosis enhance type-I IFN production via TLR-9 stimulation by hypomethylated DNA.

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“…75,76 Whether or not inflammasomes exert some sort of influence upon SLE's photosensitivity, however, is still under investigation, given that UVB radiation is capable of stimulating the synthesis of IL-1β in keratinocytes by activating the inflammasome. 77 …”

Section: Dermatological Diseases Associated With Inflammasomesmentioning

confidence: 99%

Inflammasomes and dermatology

Sá

Neto

2016

An. Bras. Dermatol.

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Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

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The inflammasome and lupus

Cited by 127 publications

References 68 publications

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils

Inflammasomes and dermatology

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