Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury

Zhang, Ling-juan; Sen, George L.; Ward, Nicole L.; Johnston, Andrew; Chun, Kimberly; Chen, Yifang; Adase, Christopher A.; Sanford, James A.; Gao, Nana; Chensee, Melanie; Sato, Emi; Fritz, Yi; Baliwag, Jaymie; Williams, Michael R.; Hata, Tissa; Gallo, Richard L.

doi:10.1016/j.immuni.2016.06.021

Cited by 145 publications

(184 citation statements)

References 51 publications

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“…Furthermore, fever promotes the recruitment and activation of immune cells (108), including IL-1-induced expansion of lymphocytes (117). Production of antimicrobial peptides provides additional means to inhibit viral replication and modulate antiviral immune responses, for example, by triggering virus aggregation or trapping, viral envelope disruption, and enhanced IFN-b production (118,119). In agreement with this, an in vivo role for IL-36a was demonstrated in a murine model of influenza pneumonia (120).…”

Section: Role In Immunity Against Virusesmentioning

confidence: 72%

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Jensen

2017

Sci. Signal.

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Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36a, IL-36b and IL-36g, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1a, IL-1b, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1a, IL-1b, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion.

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Section: Role In Immunity Against Virusesmentioning

confidence: 72%

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Jensen

2017

Sci. Signal.

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“…While dendritic cells and T cells are important cell types in the pathogenesis of psoriasis, keratinocytes have been clearly implicated as key participants in the immune response to nucleic acids, including acting as a main source of type 1 interferon production. 29 The data shows that some dsRNA complexes strongly amplify TLR3 activation while others do not. To investigate the origin of this difference, we compare the measured level of IL-6 production with the inter-dsRNA spacing and unit cell repeat number of each complex for each set of stoichiometric conditions in our phase diagram.…”

Section: Resultsmentioning

confidence: 96%

Crystallinity of Double-Stranded RNA-Antimicrobial Peptide Complexes Modulates Toll-Like Receptor 3-Mediated Inflammation

et al. 2017

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Double-stranded RNA (dsRNA) induces production of pro-inflammatory cytokines in normal human epidermal keratinocytes (NHEK) by specific binding to endosomal Toll-like receptor-3 (TLR3). Recently, it has been shown that hyperactivation of TLR3 in psoriatic keratinocytes by dsRNA can occur in the presence of human antimicrobial peptide (AMP) LL37. Here, we combine synchrotron X-ray scattering, microscopy, computer simulations, and measurements of NHEK cytokine production to elucidate a previously unanticipated form of specific molecular pattern recognition. LL37 and similar ⍺-helical AMPs can form proinflammatory nanocrystalline complexes with dsRNA that are recognized by TLR3 differently than dsRNA alone. dsRNA complexes that activate IL-6 production in NHEK and those that do not are both able to enter cells and colocalize with TLR3. However, the crystallinity of these AMP-dsRNA complexes, specifically the geometric spacing between parallel dsRNA and the repeat number of ordered dsRNA, strongly influence the level of TLR3 activation. Crystalline complexes that present dsRNA at a spacing that matches with the steric size of TLR3 can recruit and engage multiple TLR3 receptors, driving receptor clustering and immune amplification, whereas crystalline complexes that exhibit poor steric matching do not. Reverse-transcription quantitative PCR (RTqPCR) of IL-6 during siRNA knockdown of TLR3 confirms that cytokine production is due to TLR3: High levels of IL-6 transcription are observed for sterically-matched complexes without TLR3 knockdown, whereas such activity is abrogated with TLR3 knockdown.

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“…In response to pathogens or damaged-associated molecular patterns (DAMPs) released upon UVB irradiation or injury, KCs can produce large amounts of inflammatory cytokines, such as TNFα, IL6 and IFNβ, leading to immune system activation 6,7,8,9 . Although proper inflammatory signaling from KCs is required for pathogen clearance, uncontrolled inflammatory response may trigger the development of auto-inflammatory skin diseases, such as psoriasis and rosacea 6,8 .…”

Section: Introductionmentioning

confidence: 99%

Isolation and Culture of Primary Mouse Keratinocytes from Neonatal and Adult Mouse Skin

Adase

Zhang

2017

JoVE

Self Cite

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The keratinocyte (KC) is the predominant cell type in the epidermis, the outermost layer of the skin. Epidermal KCs play a critical role in providing skin defense by forming an intact skin barrier against environmental insults, such as UVB irradiation or pathogens, and also by initiating an inflammatory response upon those insults. Here we describe methods to isolate KCs from neonatal mouse skin and from adult mouse tail skin. We also describe culturing conditions using defined growth supplements (dGS) in comparison to chelexed fetal bovine serum (cFBS). Functionally, we show that both neonatal and adult KCs are highly responsive to high calcium-induced terminal differentiation, tight junction formation and stratification. Additionally, cultured adult KCs are susceptible to UVB-triggered cell death and can release large amounts of TNF upon UVB irradiation. Together, the methods described here will be useful to researchers for the setup of in vitro models to study epidermal biology in the neonatal mouse and/or the adult mouse.

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Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury

Cited by 145 publications

References 51 publications

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Crystallinity of Double-Stranded RNA-Antimicrobial Peptide Complexes Modulates Toll-Like Receptor 3-Mediated Inflammation

Isolation and Culture of Primary Mouse Keratinocytes from Neonatal and Adult Mouse Skin

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