The commensal skin microbiota triggers type I IFN–dependent innate repair responses in injured skin

Domizio, Jérémy Di; Belkhodja, Cyrine; Chenuet, Pauline; Fries, Anissa; Murray, T. J.; Mondéjar, Paula Marcos; Demaria, Olivier; Conrad, Curdin; Homey, Bernhard; Werner, Sabine; Speiser, Daniel E.; Ryffel, Bernhard; Gilliet, Michel

doi:10.1038/s41590-020-0721-6

Cited by 121 publications

(102 citation statements)

References 41 publications

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“…It has been shown that wound healing is accelerated in the absence of commensal bacteria, as the inflammation is reduced, which, in turn, promotes angiogenesis in the wound bed [106]. Conversely, several studies support a beneficial role for skin commensal bacteria in wound healing [68,82,107]. For instance, lipoteichoic acid (LTA) produced by S. epidermidis exhibits an anti-inflammatory effect on keratinocytes and restricts excessive inflammatory response upon tissue injury [19].…”

Section: The Role Of Microbiota In Wound Healingmentioning

confidence: 99%

The Immune Functions of Keratinocytes in Skin Wound Healing

Piipponen

Landén

2020

IJMS

245

139

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As the most dominant cell type in the skin, keratinocytes play critical roles in wound repair not only as structural cells but also exerting important immune functions. This review focuses on the communications between keratinocytes and immune cells in wound healing, which are mediated by various cytokines, chemokines, and extracellular vesicles. Keratinocytes can also directly interact with T cells via antigen presentation. Moreover, keratinocytes produce antimicrobial peptides that can directly kill the invading pathogens and contribute to wound repair in many aspects. We also reviewed the epigenetic mechanisms known to regulate keratinocyte immune functions, including histone modifications, non-protein-coding RNAs (e.g., microRNAs, and long noncoding RNAs), and chromatin dynamics. Lastly, we summarized the current evidence on the dysregulated immune functions of keratinocytes in chronic nonhealing wounds. Based on their crucial immune functions in skin wound healing, we propose that keratinocytes significantly contribute to the pathogenesis of chronic wound inflammation. We hope this review will trigger an interest in investigating the immune roles of keratinocytes in chronic wound pathology, which may open up new avenues for developing innovative wound treatments.

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Section: The Role Of Microbiota In Wound Healingmentioning

confidence: 99%

The Immune Functions of Keratinocytes in Skin Wound Healing

Piipponen

Landén

2020

IJMS

245

139

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“…Several studies have highlighted that the skin commensal microbiota play important functions in the regulation of wound healing and in the innate immune defense against infection (144)(145)(146). In fact, using longitudinal transcriptional profiling, Grice et al found a shift in the wound microbiota of diabetic mice, and found this shift correlated with impaired healing and a prolonged inflammatory response (75).…”

Section: General Host Response To Bacteria or Bacterial Components In Woundsmentioning

confidence: 99%

Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation

et al. 2021

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Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular disease, and cancer. These delays increase a patient’s risk for infection and, in severe cases, can result in the formation of chronic, non-healing ulcers (e.g., diabetic foot ulcers, surgical site infections, pressure ulcers and venous leg ulcers). Chronic wounds are very difficult and expensive to treat and there is an urgent need to develop more effective therapeutics that restore healing processes. Sustained innate immune activation and inflammation are common features observed across most chronic wound types. However, the factors driving this activation remain incompletely understood. Emerging evidence suggests that the composition and structure of the wound microbiome may play a central role in driving this dysregulated activation but the cellular and molecular mechanisms underlying these processes require further investigation. In this review, we will discuss the current literature on: 1) how bacterial populations and biofilms contribute to chronic wound formation, 2) the role of bacteria and biofilms in driving dysfunctional innate immune responses in chronic wounds, and 3) therapeutics currently available (or underdevelopment) that target bacteria-innate immune interactions to improve healing. We will also discuss potential issues in studying the complexity of immune-biofilm interactions in chronic wounds and explore future areas of investigation for the field.

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“…16,17 However, we show here that commensal skin bacteria are required as source of nucleic acid in order to induce relevant pDC activation and type I IFN production in vivo, in line with similar observations from skin wound healing. 33 These ndings suggest that bacteria have several key pathogenic roles in rosacea: 1) They activate TLR2 on KCs to upregulate KLK5, 2) provide an essential source for nucleic acid in order to activate pDCs to produce type I IFN and initiate a pathogenic in ammation, and 3) activate neutrophils through cell surface-TLRs. 8 Therefore, bacteria are essential for the activation of the KLK5 -cathelicidin -pDC/type I IFN axis.…”

Section: Discussionmentioning

confidence: 99%

Type I interferons link skin-associated dysbiotic commensal bacteria to pathogenic inflammation and angiogenesis in rosacea

Mylonas

Hawerkamp

Wang

et al. 2021

Preprint

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Rosacea is a common chronic inflammatory skin disease that is characterized by a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with high density of B. oleronius and increased activity of the serine protease kallikrein 5, which cleaves cathelicidin antimicrobial peptide, have been recognized as key pathogenic triggers in rosacea. However, how these events are linked to the hallmarks of the disease remains unknown. Here, we show that type I interferons produced by plasmacytoid dendritic cells represent the pivotal link between dysbiosis, an aberrant immune response, and neovascularization in rosacea. In fact, compared to other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides leading to enhanced generation of complexes with DNA. DNA from skin-associated microbiota but not from host cells is required for cathelicidin-induced activation of plasmacytoid dendritic cells and type I-interferon production, which is further amplified by B. oleronius. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA binding and type I interferon-inducing capacities, further facilitating type I interferon production within the skin. In turn, type I interferons induce IL22 whilst simultaneously rendering endothelial cells responsive through upregulation of the IL22-receptor, and thereby driving drive neoangiogenesis. These findings unravel novel pathomechanisms, which directly link several hallmarks of rosacea to the killing of dysbiotic commensal bacteria and the induction of a pathogenic type-I interferon-TH17/22 pathway.

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The commensal skin microbiota triggers type I IFN–dependent innate repair responses in injured skin

Cited by 121 publications

References 41 publications

The Immune Functions of Keratinocytes in Skin Wound Healing

The Immune Functions of Keratinocytes in Skin Wound Healing

Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation

Type I interferons link skin-associated dysbiotic commensal bacteria to pathogenic inflammation and angiogenesis in rosacea

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