Lupus Skin Is Primed for IL-6 Inflammatory Responses through a Keratinocyte-Mediated Autocrine Type I Interferon Loop

Stannard, Jasmine; Reed, T. Edward; Myers, Emily M.; Lowe, Lori; Sarkar, Mrinal K.; Xing, Xianying; Guðjónsson, Jóhann E.; Kahlenberg, J. Michelle

doi:10.1016/j.jid.2016.09.008

Cited by 80 publications

(90 citation statements)

References 46 publications

(52 reference statements)

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“…Cutaneous lupus lesions are marked by strong type I IFN signatures(38, 39) and monocyte infiltration of lesions(40, 41). In order to confirm relevance of caspase-1 and IRF1 dysregulation in an SLE disease phenotype, expression of both genes were assessed in lesional skin biopsies from 47 discoid lupus erythematosus (DLE) and 43 subacute cutaneous lupus erythematosus (SCLE) patients and from 13 normal control biopsies.…”

Section: Resultsmentioning

confidence: 99%

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Liu

Berthier

Kahlenberg

2017

Arthritis & Rheumatology

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Objective The inflammasome complex is a driver of organ damage in systemic lupus erythematosus (SLE). While type I interferons (IFNs) are well established as mediators of SLE pathogenesis, their role in inflammasome activation in SLE has not been assessed. Thus, we examined type I IFNs as regulators of the inflammasome and identified interferon regulatory factor 1 (IRF1) as critical for inflammasome hyperactivity in SLE. Methods SLE patients fulfilled ≥4 ACR criteria and were recruited from the University of Michigan Lupus Cohort. Primary monocytes were isolated from SLE patients or healthy controls by negative selection, treated with inflammasome activators in the presence or absence of IFNα, and IL-1β secretion was measured by ELISA. Expression levels of interferon and inflammasome-related molecules were assessed by real-time PCR and Western blotting. IRF1 expression was specifically downregulated by siRNA transfection and a chemical inhibitor. Results SLE monocytes exhibited increased expression and enhanced activation of the inflammasome by ATP when compared to control monocytes. Expression of inflammasome and interferon-regulated genes was significantly correlated in lupus, but not control, monocytes. Inflammasome activity was increased after prolonged exposure to IFNα. Reduction of IRF1 expression via siRNA blocked caspase-1 upregulation after treatment with IFNα. Importantly, hyperactivity of the inflammasome in lupus monocytes was significantly reduced after knock-down or inhibition of IRF1. Conclusion Prolonged type I IFN exposure, as seen in SLE patients, primes monocytes for robust inflammasome activation in an IRF1-dependent manner. IRF1 inhibition may serve as a novel target for treatment of SLE-associated inflammation and organ damage.

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Section: Resultsmentioning

confidence: 99%

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Liu

Berthier

Kahlenberg

2017

Arthritis & Rheumatology

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“…The recruitment of DO11 Th1 cells to the skin can then presumably drive a chronic response by provoking continuous KC death and potentially KC chemokine/cytokine production. KCs also make their own unique form of type I IFN, IFN-κ, which may also contribute to the strong Th1 phenotype of the infiltrating T cells (7). Whether TLR9 deficiency in KCs per se contributes to disease amplification will need to be addressed through the analysis of Ii-TGO mice with KC-specific deletion of TLR9.…”

Section: Discussionmentioning

confidence: 99%

“…The most common cutaneous lesions in CLE patients are characterized histologically as interface dermatitis associated with epidermal basal-cell damage, apoptosis of keratinocytes (KCs), and a variable subepithelial inflammatory infiltrate in the skin that includes cytotoxic Th1 cells and plasmacytoid dendritic cells (pDCs) (2)(3)(4)(5). Common pathophysiological mechanisms, including proinflammtory type 1 IFN, are thought to promote CLE and other clinical manifestations of SLE (7). Therefore, a better understanding of the genetic, environmental, and immunoregulatory factors that drive CLE is likely to provide important insights for the treatment of both CLE and SLE.…”

Section: Introductionmentioning

confidence: 99%

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation

Mande¹,

Zirak²,

Ko³

et al. 2018

Journal of Clinical Investigation

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Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.

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“…In SLE patients, keratinocytes have been implicated in the pathogenesis of skin injury by undergoing apoptosis or necrosis and eventually releasing autoantigens (73). Previous studies demonstrated that keratinocytes from patients with cutaneous lupus erythematosus presented increased production of IL-6 compared to healthy controls, with type I IFNs enhancing this process (74). In addition, IFNK expression was reported to be significantly increased in lesional skin of patients with cutaneous lupus erythematosus related to photosensitivity (75) In summary, while the importance of type I IFN in SLE is undeniable, the reasons for the failure of normal regulation of its production have never been clear.…”

Section: Recent Findings On Systemic Sclerosis Reported the Abnormal mentioning

confidence: 99%

Plasmacytoid dendritic cells are functionally exhausted while non-haematopoietic sources of type I interferon dominate human autoimmunity

Psarras

Alase

Antanaviciute

et al. 2018

Preprint

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Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons (IFNs) have a crucial role in the progression to established autoimmune diseases such as systemic lupus erythematosus (SLE). However, their cellular source and regulation in disease initiation are unclear. The current paradigm suggests that plasmacytoid dendritic cells (pDCs) are activated in SLE contributing to excessive IFN production. Here, we show that in preclinical autoimmunity, established SLE, and primary Sjögren's Syndrome, pDCs are not effector cells, but rather have lost their capacity for TLR-mediated IFNα and TNF production and fail to induce T cell activation, independently of disease activity and blood IFN signature. In addition, pDCs present a transcriptional signature of cellular stress and senescence accompanied by increased telomere erosion.Instead, we demonstrate a marked enrichment of IFN signature in non-lesional skin in preclinical autoimmunity. In these individuals and SLE patients, type I IFNs were abundantly produced by keratinocytes in the absence of infiltrating leucocytes. These findings revise our understanding of the role of IFN in the initiation of human autoimmunity, with non-haematopoietic tissues perpetuating IFN responses, which in turn predict clinical disease. These data indicate potential therapeutic targets outside the conventional immune system for treatment and prevention.

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Lupus Skin Is Primed for IL-6 Inflammatory Responses through a Keratinocyte-Mediated Autocrine Type I Interferon Loop

Cited by 80 publications

References 46 publications

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation

Plasmacytoid dendritic cells are functionally exhausted while non-haematopoietic sources of type I interferon dominate human autoimmunity

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