SIGIRR Negatively Regulates IL-36–Driven Psoriasiform Inflammation and Neutrophil Infiltration in the Skin

Giannoudaki, Eirini; Stefańska, Anna; Lawler, Hazel; Leon, Gemma; Hernandez-Santana, Yasmina; Hassan, Najma; Russell, Shane E.; Horan, Rachel M.; Sweeney, Cheryl; Preston, Roger J. S.; Mantovani, Alberto; Garlanda, Cecilia; Fallon, Padraic G.; Walsh, Patrick

doi:10.4049/jimmunol.2100237

Cited by 13 publications

(11 citation statements)

References 48 publications

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“…For instance, IL-18 and IL-36 were also found at high concentrations in our keratinocyte extracts. While IL-18 is mostly associated with macrophage recruitment in vivo ( 15 ), IL-36 has been reported to attract neutrophils in the skin ( 28 ). Altogether, our results are in accordance with the previous studies reporting the contribution of IL-1 in sterile inflammation induced by dying cells ( 15 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

Dermal fibroblasts are the key sensors of aseptic skin inflammation through interleukin 1 release by lesioned keratinocytes

Cordier-Dirikoc¹,

Pedretti²,

Garnier³

et al. 2022

Front. Immunol.

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IL-1 plays a crucial role in triggering sterile inflammation following tissue injury. Although most studies associate IL-1 release by injured cells to the recruitment of neutrophils for tissue repair, the inflammatory cascade involves several molecular and cellular actors whose role remains to be specified. In the present study, we identified dermal fibroblasts among the IL-1R1-expressing skin cells as key sensors of IL-1 released by injured keratinocytes. After in vitro stimulation by recombinant cytokines or protein extracts of lysed keratinocytes containing high concentrations of IL-1, we show that dermal fibroblasts are by far the most IL-1-responsive cells compared to keratinocytes, melanocytes and endothelial cells. Fibroblasts have the property to respond to very low concentrations of IL-1 (from 10 fg/ml), even in the presence of 100-fold higher concentrations of IL-1RA, by increasing their expression of chemokines such as IL-8 for neutrophil recruitment. The capacity of IL-1-stimulated fibroblasts to attract neutrophils has been demonstrated both in vitro using cell migration assay and in vivo using a model of superficial epidermal lesion in IL-1R1-deficient mice which harbored reduced expression of inflammatory mediators and neutrophil skin infiltration. Together, our results shed a light on dermal fibroblasts as key relay cells in the chain of sterile inflammation induced after epidermal lesion.

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Section: Discussionmentioning

confidence: 99%

Dermal fibroblasts are the key sensors of aseptic skin inflammation through interleukin 1 release by lesioned keratinocytes

Cordier-Dirikoc¹,

Pedretti²,

Garnier³

et al. 2022

Front. Immunol.

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“…challenge and SIGIRR of grass carp after Flavobacterium cloumnare challenge (29,30), suggesting that DIGIRR or SIGIRR had similar functions during bacterial infection. Mammalian SIGIRR could negatively regulate the TLRs signaling pathway, by competitively interacting with the adaptor molecules (such as MyD88, IRAKs and TRAF6) through its TIR domain to weaken the excessive TLRs response (55)(56)(57). Whilst, zebrafish SIGIRR could not only interact with MyD88 in HEK-293T cells, but also interact with TRIF protein in vitro and zebrafish embryo cells, playing important roles in inhibiting the liver inflammation of zebrafish (26).…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization and functional analysis of DIGIRR from golden pompano (Trachinotus ovatus)

Xie

Gao²,

Cao³

et al. 2022

Front. Immunol.

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Mammalian single immunoglobulin (Ig) interleukin-1 receptor related molecule (SIGIRR), an important member of the Toll/interleukin-1 receptor (TIR) family, plays important balancing roles in the inflammatory responses. In the present study, the double Ig interleukin-1 receptor related molecule (DIGIRR), the homologous of SIGIRR, was characterized in golden pompano (Trachinotus ovatus) (termed as trDIGIRR). The full-length cDNA of trDIGIRR was 2,167 bp with an open reading frame (ORF) of 1,572 bp encoding 523 amino acids. The trDIGIRR contained several conserved domains including a signal peptide, two Ig domains, a transmembrane domain and a TIR domain, and shared high sequence identities with its teleost counterparts. Realtime qPCR analysis revealed that the trDIGIRR was distributed in all tissues examined, with high expressions in intestine, liver and head kidney. The expressions of trDIGIRR were induced by Vibrio alginolyticus, lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (poly I:C) challenge. Further analysis revealed that trDIGIRR was mainly located in the cytoplasm. In addition, the co-immunoprecipitation (co-IP) assay identified that trDIGIRR could interact with myeloid differentiation factor 88 (MyD88), but not interact with TIR domain containing adaptor protein inducing interferon-β (TRIF). Our results provide basis for studying the immune role of fish DIGIRR.

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“…IL‐36 cytokines have a strong ability to recruit neutrophils to the skin 87 and, in turn, neutrophil‐derived proteases process IL‐36 cytokines, enhancing their biological activity 88 . This suggests that neutrophils are key players in escalating IL‐36‐driven inflammation, and that IL‐36 may be central to the pathogenesis of NDs 16 .…”

Section: Interleukin‐36 In Skin Diseasesmentioning

confidence: 99%

Therapeutic potential of targeting interleukin‐1 family cytokines in chronic inflammatory skin diseases*

et al. 2022

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Summary The interleukin (IL)‐1 family of cytokines is a central regulator of a myriad of immunological responses. It comprises several cytokines, including those belonging to the IL‐1, IL‐36 and IL‐18 subfamilies, as well as IL‐33. The IL‐1 family primarily plays a role in orchestrating innate immune responses, but is also involved in adaptive immunity. Increased interest in the IL‐1 family occurred following the discovery that dysregulation of IL‐1 signalling underlies the pathogenesis of several monogenic autoinflammatory diseases, characterized by sterile inflammation involving the skin and other organs. This also provided increased understanding of the role of innate immunity and the IL‐1 family in polygenic autoinflammatory skin conditions, such as neutrophilic dermatoses, as well as in some of the most common chronic inflammatory skin diseases, such as psoriasis and hidradenitis suppurativa. Several therapeutic agents have been developed to inhibit the IL‐1 family members and their signalling pathways. These have shown therapeutic efficacy in several chronic inflammatory skin disorders. The aim of this review is to thoroughly describe the consequences of pathological dysregulation of the IL‐1, IL‐33, IL‐36 and IL‐18 pathways in dermatological conditions and to provide a forward‐looking update on therapeutic strategies targeting signalling by IL‐1 family cytokines.

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SIGIRR Negatively Regulates IL-36–Driven Psoriasiform Inflammation and Neutrophil Infiltration in the Skin

Cited by 13 publications

References 48 publications

Dermal fibroblasts are the key sensors of aseptic skin inflammation through interleukin 1 release by lesioned keratinocytes

Dermal fibroblasts are the key sensors of aseptic skin inflammation through interleukin 1 release by lesioned keratinocytes

Molecular characterization and functional analysis of DIGIRR from golden pompano (Trachinotus ovatus)

Therapeutic potential of targeting interleukin‐1 family cytokines in chronic inflammatory skin diseases*

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