Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis

Herster, Franziska; Bittner, Zsofia; Archer, Nathan K.; Dickhöfer, Sabine; Eisel, David; Eigenbrod, Tatjana; Knorpp, Thomas; Schneiderhan‐Marra, Nicole; Löffler, Markus; Kalbacher, Hubert; Vierbuchen, Tim; Heine, Holger; Miller, Lloyd S.; Hartl, Dominik; Freund, Lukas; Schäkel, Knut; Heister, Martin; Ghoreschi, Kamran; Weber, Alexander N.R.

doi:10.1038/s41467-019-13756-4

Cited by 158 publications

(184 citation statements)

References 58 publications

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“…However, NETs have also been shown to form through a TLR 7/8/9 mediated pathway that is independent of PAD4 via secondary self-propagation. 17,24 That is, nucleic acid material present in the tissue stimulates the TLR7/8/9 receptors of immune cells, which triggers additional inflammation and a second wave of neutrophils and NETs. We have shown that NETs were abundant in the injured tissue, which may go on to contribute to secondary NETosis.…”

Section: Discussionmentioning

confidence: 99%

“…23 Recent reports suggest that NET formation also occurs when DNA and RNA stimulate toll-like receptors (TLR) on polymorphonuclear neutrophils in a process termed self-propagation or secondary NETosis. 17,24 TLR 7/8 and 9 are pattern recognition receptors expressed on cells of the innate immune system, which are classically believed to recognize pathogenic RNA and DNA, respectively. However, growing evidence suggests that aberrant activation of these TLRs with self DNA and/or RNA occur when free nucleic material is present in the tissue, such as in autoimmune diseases, viral infections, and following traumatic injuries.…”

Section: Introductionmentioning

confidence: 99%

“…17,[25][26][27][28][29][30][31] Small molecule inhibitors of TLR7/8/9, such as hydroxychloroquine (HCQ, Plaquenil®), were developed initially as anti-malarial agents, but have shown to be efficacious for treating lupus, an autoimmune disease characterized by excess and impaired degradation of NETs. 13,24,[32][33][34] HCQ has also been shown to be an effective antiviral agent against RNA viruses including dengue virus and retroviruses 35 by de-acidifying endosomes required for endosome-mediated viral entry during TLR7/8/9 activation.…”

Section: Introductionmentioning

confidence: 99%

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The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury

et al. 2020

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Ischemia reperfusion (IR) injury results in devastating skeletal muscle fibrosis. Here, we recapitulate this injury with a mouse model of hindlimb IR injury which leads to skeletal muscle fibrosis. Injury resulted in extensive immune infiltration with robust neutrophil extracellular trap (NET) formation in the skeletal muscle, however, direct targeting of NETs via the peptidylarginine deiminase 4 (PAD4) mechanism was insufficient to reduce muscle fibrosis. Circulating levels of IL-10 and TNFα were significantly elevated post injury, indicating toll-like receptor (TLR) signaling may be involved in muscle injury. Administration of hydroxychloroquine (HCQ), a small molecule inhibitor of TLR7/8/9, following injury reduced NET formation, IL-10, and TNFα levels and ultimately mitigated muscle fibrosis and improved myofiber regeneration following IR injury. HCQ treatment decreased fibroadipogenic progenitor cell proliferation and partially inhibited ERK1/2 phosphorylation in the injured tissue, suggesting it may act through a combination of TLR7/8/9 and ERK signaling mechanisms. We demonstrate that treatment with FDA-approved HCQ leads to decreased muscle fibrosis and increased myofiber regeneration following IR injury, suggesting short-term HCQ treatment may be a viable treatment to prevent muscle fibrosis in ischemia reperfusion and traumatic extremity injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury

et al. 2020

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“…This raises the possibility that neutrophils are involved in the pathogenesis of psoriasis via NETosis following Th17 activation. On the other hand, Herster et al reported that LL-37 in complex with RNA induced the release of NETs via TLR8/TLR13-mediated cytokine, whereas LL-37 in complex with DNA did not [79]. Moreover, AMPs have been detected in mast cell extracellular traps (MCETs), which are similar to NETs [80].…”

Section: Neutrophils Neutrophil Extracellular Traps (Nets) and Ampsmentioning

confidence: 99%

Psoriasis and Antimicrobial Peptides

Takahashi

Yamasaki

2020

IJMS

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Psoriasis is a systemic inflammatory disease caused by crosstalk between various cells such as T cells, neutrophils, dendritic cells, and keratinocytes. Antimicrobial peptides (AMPs) such as β-defensin, S100, and cathelicidin are secreted from these cells and activate the innate immune system through various mechanisms to induce inflammation, thus participating in the pathogenesis of psoriasis. In particular, these antimicrobial peptides enhance the binding of damage-associated molecular patterns such as self-DNA and self-RNA to their receptors and promote the secretion of interferon from activated plasmacytoid dendritic cells and keratinocytes to promote inflammation in psoriasis. Neutrophil extracellular traps (NETs), complexes of self-DNA and proteins including LL-37 released from neutrophils in psoriatic skin, induce Th17. Activated myeloid dendritic cells secrete a mass of inflammatory cytokines such as IL-12 and IL-23 in psoriasis, which is indispensable for the proliferation and survival of T cells that produce IL-17. AMPs enhance the production of some of Th17 and Th1 cytokines and modulate receptors and cellular signaling in psoriasis. Inflammation induced by DAMPs, including self-DNA and RNA released due to microinjuries or scratches, and the enhanced recognition of DAMPs by AMPs, may be involved in the mechanism underlying the Köbner phenomenon in psoriasis.

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“…A recent study also demonstrates the role of cathelicidin from infiltrating neutrophils in the disease. Complexes of cathelicidin with RNA that are rich in psoriatic skin trigger via TLR8/TLR13 inflammatory cytokine production by neutrophils and the formation of NETs perpetuating chronic inflammation in psoriasis ( 66 ). In addition to activating the innate immune system, cathelicidin was identified as an autoantigen with the presence of cathelicidin-specific T cells that produce IFN-gamma in the skin of patients with psoriasis ( 67 ).…”

Section: The Role Of Amps In Autoimmune Diseasementioning

confidence: 99%

The Dual Role of Antimicrobial Peptides in Autoimmunity

Liang

Diana

2020

Front. Immunol.

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Autoimmune diseases (AiDs) are characterized by the destruction of host tissues by the host immune system. The etiology of AiDs is complex, with the implication of multiple genetic defects and various environmental factors (pathogens, antibiotic use, pollutants, stress, and diet). The interaction between these two compartments results in the rupture of tolerance against self-antigens and the unwanted activation of the immune system. Thanks to animal models, the immunopathology of many AiDs is well described, with the implication of both the innate and adaptive immune systems. This progress toward the understanding of AiDs led to several therapies tested in patients. However, the results from these clinical trials have not been satisfactory, from reversing the course of AiDs to preventing them. The need for a cure has prompted many investigators to explore alternative aspects in the immunopathology of these diseases. Among these new aspects, the role of antimicrobial host defense peptides (AMPs) is growing. Indeed, beyond their antimicrobial activity, AMPs are potent immunomodulatory molecules and consequently are implicated in the development of numerous AiDs. Importantly, according to the disease considered, AMPs appear to play a dual role in autoimmunity with either anti- or pro-inflammatory abilities. Here, we aimed to summarize the current knowledge about the role of AMPs in the development of AiDs and attempt to provide some hypotheses explaining their dual role. Definitely, a complete understanding of this aspect is mandatory before the design of AMP-based therapies against AiDs.

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Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis

Cited by 158 publications

References 58 publications

The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury

The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury

Psoriasis and Antimicrobial Peptides

The Dual Role of Antimicrobial Peptides in Autoimmunity

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