Abstract
In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components. Moreover, the importance of IL-1 has been reported for an increasing number of autoinflammatory skin diseases including but not limited to deficiency of IL-1 receptor antagonist, mevalonate kinase deficiency and PAPA syndrome. Recent findings have revealed that excessive IL-1 release induced by harmful stimuli likely contributes to the pathogenesis of common dermatological diseases such as acne vulgaris or seborrheic dermatitis. A key pathogenic feature of these diseases is IL-1β-induced neutrophil recruitment to the skin. IL-1β blockade may therefore represent a promising therapeutic approach. Several case reports and clinical trials have demonstrated the efficacy of IL-1 inhibition in the treatment of these skin disorders. Next to the recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra and the soluble decoy Rilonacept, the anti-IL-1α monoclonal antibody MABp1 and anti-IL-1β Canakinumab but also Gevokizumab, LY2189102 and P2D7KK, offer valid alternatives to target IL-1. Although less thoroughly investigated, an involvement of IL-18 in the development of cutaneous inflammatory disorders is also suspected. The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases.
Highlights
The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases
Thanks to the discovery of the inflammasome and to major advances in the understanding of biological properties and clinical relevance of IL-1 family members,’ the use of IL1 antagonists has been quite intensely investigated for the treatment of inflammatory and autoinflammatory diseases (Table 2)
The introduction of IL-1 antagonists represents a major breakthrough in the management of several autoinflammatory diseases, including cryopyrinopathies and other inflammatory conditions refractory to standard therapies where neutrophils play an important pathogenic role
Summary
Pathogen recognition is fulfilled by a distinct set of receptors, the so-called pathogen-recognition receptors (PRRs) These include C-type lectin receptors (CLRs), Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), AIM2-like receptors (ALRs), and partially the complement system. Such PRRs have different localizations and ligands. NLRs constitute an expanding family of receptors able to detect a variety of molecules They are composed of several domains: the central NOD or nucleotide-binding domain (NBD) that includes a NTPase NACHT domain controlling self-oligomerization, and the leucine-rich repeat (LRR) domain involved in ligand sensing (Schroder and Tschopp, 2010). On their N-terminal extremity, NLRs have either a pyrin domain (PYD), a caspase-recruitment domain (CARD) or a baculoviral inhibition of apoptosis protein repeat domain (BIR) and are named NLRPs, NRLCs or NAIPs, respectively
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