IL-1 Family Antagonists in Mouse and Human Skin Inflammation

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Apr 2

PMID 33796114

Citations 27

Authors

Praxedis Martin

Jeremie D Goldstein

Loic Mermoud

Alejandro Diaz-Barreiro

Gaby Palmer

Affiliations

Soon will be listed here.

Abstract

Interleukin (IL)-1 family cytokines initiate inflammatory responses, and shape innate and adaptive immunity. They play important roles in host defense, but excessive immune activation can also lead to the development of chronic inflammatory diseases. Dysregulated IL-1 family signaling is observed in a variety of skin disorders. In particular, IL-1 family cytokines have been linked to the pathogenesis of psoriasis and atopic dermatitis. The biological activity of pro-inflammatory IL-1 family agonists is controlled by the natural receptor antagonists IL-1Ra and IL-36Ra, as well as by the regulatory cytokines IL-37 and IL-38. These four anti-inflammatory IL-1 family members are constitutively and highly expressed at steady state in the epidermis, where keratinocytes are a major producing cell type. In this review, we provide an overview of the current knowledge concerning their regulatory roles in skin biology and inflammation and their therapeutic potential in human inflammatory skin diseases. We further highlight some common misunderstandings and less well-known observations, which persist in the field despite recent extensive interest for these cytokines.

Citing Articles

The role of the interleukin family in liver fibrosis.

Zhang Z, Wang J, Li H, Niu Q, Tao Y, Zhao X Front Immunol. 2025; 16:1497095.

PMID: 39995661 PMC: 11847652. DOI: 10.3389/fimmu.2025.1497095.

Full-length and N-terminally truncated recombinant interleukin-38 variants are similarly inefficient in antagonizing interleukin-36 and interleukin-1 receptors.

Diaz-Barreiro A, Talabot-Ayer D, Huard A, Cereghetti G, Tonacini J, Maillasson M Cell Commun Signal. 2025; 23(1):34.

PMID: 39833821 PMC: 11744908. DOI: 10.1186/s12964-025-02035-z.

Exploring the effect of hsa-miR-19b-3p on IL-1R1 expression and serum levels in alopecia areata.

AbdElneam A, Al-Dhubaibi M, Bahaj S, Mohammed G, Atef L Arch Dermatol Res. 2025; 317(1):284.

PMID: 39825934 DOI: 10.1007/s00403-024-03788-2.

Life stage impact on the human skin ecosystem: lipids and the microbial community.

Pagac M, Davient B, Plado L, Lam H, Lee S, Ravikrishnan A NPJ Biofilms Microbiomes. 2025; 11(1):13.

PMID: 39800795 PMC: 11725588. DOI: 10.1038/s41522-025-00652-7.

Intraperitoneal Injection of the Outer Membrane Vesicle (OMV) Stimulated Expressions of Neuroinflammatory Markers and Histopathological Changes in the Brains of Adult Zebrafish.

Adewoyin M, Hamarsha A, Akinsola R, Teoh S, Azmai M, Abu Bakar N Int J Mol Sci. 2024; 25(20).

PMID: 39456807 PMC: 11506875. DOI: 10.3390/ijms252011025.

References

Eisenmesser E, Gottschlich A, Redzic J, Paukovich N, Nix J, Azam T . Interleukin-37 monomer is the active form for reducing innate immunity. Proc Natl Acad Sci U S A. 2019; 116(12):5514-5522. PMC: 6431183. DOI: 10.1073/pnas.1819672116. View

Smithrithee R, Niyonsaba F, Kiatsurayanon C, Ushio H, Ikeda S, Okumura K . Human β-defensin-3 increases the expression of interleukin-37 through CCR6 in human keratinocytes. J Dermatol Sci. 2014; 77(1):46-53. DOI: 10.1016/j.jdermsci.2014.12.001. View

Boutet M, Bart G, Penhoat M, Amiaud J, Brulin B, Charrier C . Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease. Clin Exp Immunol. 2015; 184(2):159-73. PMC: 4837235. DOI: 10.1111/cei.12761. View

Palmer G, Lipsky B, Smithgall M, Meininger D, Siu S, Talabot-Ayer D . The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine. 2008; 42(3):358-64. DOI: 10.1016/j.cyto.2008.03.008. View

Kanangat S, Postlethwaite A, Higgins G, Hasty K . Novel functions of intracellular IL-1ra in human dermal fibroblasts: implications in the pathogenesis of fibrosis. J Invest Dermatol. 2006; 126(4):756-65. DOI: 10.1038/sj.jid.5700097. View

Shanmugam V, Jones D, McNish S, Bendall M, Crandall K . Transcriptome patterns in hidradenitis suppurativa: support for the role of antimicrobial peptides and interferon pathways in disease pathogenesis. Clin Exp Dermatol. 2019; 44(8):882-892. DOI: 10.1111/ced.13959. View

Barton J, Herbst R, Bosisio D, Higgins L, Nicklin M . A tissue specific IL-1 receptor antagonist homolog from the IL-1 cluster lacks IL-1, IL-1ra, IL-18 and IL-18 antagonist activities. Eur J Immunol. 2000; 30(11):3299-308. DOI: 10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO;2-S. View

Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U . An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009; 360(23):2438-44. PMC: 2803085. DOI: 10.1056/NEJMoa0809568. View

Kim H, Kim S, Park J, Lee M, Kim D, Lee M . Up-regulation of receptor antagonist interleukin-1 family members in psoriasis and their regulation by pro-inflammatory cytokines. J Dermatol Sci. 2016; 82(3):204-6. DOI: 10.1016/j.jdermsci.2016.02.003. View

10.

Onoufriadis A, Simpson M, Pink A, Di Meglio P, Smith C, Pullabhatla V . Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. 2011; 89(3):432-7. PMC: 3169817. DOI: 10.1016/j.ajhg.2011.07.022. View

11.

Gunther S, Sundberg E . Molecular determinants of agonist and antagonist signaling through the IL-36 receptor. J Immunol. 2014; 193(2):921-30. DOI: 10.4049/jimmunol.1400538. View

12.

Goleva E, Berdyshev E, Leung D . Epithelial barrier repair and prevention of allergy. J Clin Invest. 2019; 129(4):1463-1474. PMC: 6436854. DOI: 10.1172/JCI124608. View

13.

Bal E, Lim A, Shen M, Douangpanya J, Madrange M, Gazah R . Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome. Exp Dermatol. 2017; 28(10):1114-1117. DOI: 10.1111/exd.13387. View

14.

Hao J . Targeting interleukin-22 in psoriasis. Inflammation. 2013; 37(1):94-9. DOI: 10.1007/s10753-013-9715-y. View

15.

Mee J, Antonopoulos C, Poole S, Kupper T, Groves R . Counter-regulation of interleukin-1alpha (IL-1alpha) and IL-1 receptor antagonist in murine keratinocytes. J Invest Dermatol. 2005; 124(6):1267-74. DOI: 10.1111/j.0022-202X.2005.23684.x. View

16.

Milora K, Fu H, Dubaz O, Jensen L . Unprocessed Interleukin-36α Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1. J Invest Dermatol. 2015; 135(12):2992-3000. PMC: 4648684. DOI: 10.1038/jid.2015.289. View

17.

Johnston A, Xing X, Wolterink L, Barnes D, Yin Z, Reingold L . IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis. J Allergy Clin Immunol. 2017; 140(1):109-120. PMC: 5494022. DOI: 10.1016/j.jaci.2016.08.056. View

18.

Pasparakis M, Haase I, Nestle F . Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol. 2014; 14(5):289-301. DOI: 10.1038/nri3646. View

19.

Gabay C, Porter B, Fantuzzi G, Arend W . Mouse IL-1 receptor antagonist isoforms: complementary DNA cloning and protein expression of intracellular isoform and tissue distribution of secreted and intracellular IL-1 receptor antagonist in vivo. J Immunol. 1998; 159(12):5905-13. View

20.

Sugiura K, Takeichi T, Kono M, Ogawa Y, Shimoyama Y, Muro Y . A novel IL36RN/IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis. Br J Dermatol. 2012; 167(3):699-701. DOI: 10.1111/j.1365-2133.2012.10953.x. View