IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

Abstract

Over 20 years ago, it was first proposed that autoinflammation underpins a handful of rare monogenic disorders characterized by recurrent fever and systemic inflammation. The subsequent identification of novel, causative genes directly led to a better understanding of how the innate immune system is regulated under normal conditions, as well as its dysregulation associated with pathogenic mutations. Early on, IL-1 emerged as a central mediator for these diseases, based on data derived from patient cells, mutant mouse models and definitive clinical responses to IL-1 targeted therapy. Since that time, our understanding of the mechanisms of autoinflammation has expanded beyond IL-1 to additional innate immune processes. However, the number and complexity of IL-1-mediated autoinflammatory diseases has also multiplied to include additional monogenic syndromes with expanded genotypes and phenotypes, as well as more common polygenic disorders seen frequently by the practising clinician. In order to increase physician awareness and update rheumatologists who are likely to encounter these patients, this review discusses the general pathophysiological concepts of IL-1-mediated autoinflammation, the epidemiological and clinical features of specific diseases, diagnostic challenges and approaches, and current and future perspectives for therapy.

Fig. 1. Timeline of key events leading to current understanding and treatment of IL-1-mediated autoinflammatory diseases.

First described as pyrexin in 1943, and subsequently termed lymphocyte-activating factor and leukocytic pyrogen in the 1970s, the introduction of interleukin nomenclature united these secreted macrophage products as IL-1. The timeline shows scientific advances in yellow, the first identification of a specific gene as the cause of a given autoinflammatory syndrome in grey, and the initial approval for IL-1-targeted therapies (with agency) in red. AOSD, adult-onset Still disease; CAPS, cryopyrin-associated periodic syndromes; DIRA, deficiency of IL1 receptor antagonist; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; GSDMD, gasdermin D; HIDS, hyper IgD syndrome; MKD, mevalonate kinase deficiency; MWS, Muckle–Wells syndrome; NOMID, neonatal-onset multisystem inflammatory disease; PAPA, pyogenic arthritis, pyoderma gangrenosum and acne syndrome; RA, rheumatoid arthritis; sJIA, systemic juvenile idiopathic arthritis; Syn, syndrome; TRAPS, tumour necrosis factor receptor-associated periodic syndrome; UK, Medicines and Healthcare Products Regulatory Agency of the United Kingdom.

Fig. 2. Mechanisms of IL-1-mediated inflammation and targets for therapy.

The expression, release and functional consequences of IL-1β and IL-1α are intertwined and highly regulated at multiple levels. Many upstream mechanisms, which can be grouped into damage- and pathogen-associated molecular patterns (DAMPs and PAMPs), trigger the activation of the inflammasome, an intracellular complex of multiple proteins (such as NLRC4, NLRP1, pyrin and NLRP3). Activation of the inflammasome, in turn, activates the caspase enzymes 1, 4 and 5, and other proteases, which process (cleave) and activate IL-1β and IL-1α. Non-inflammasome pathways can also activate caspase 8. Upon activation, IL-1β and IL-1α are released from the cell via a gasdermin E lytic process, gasdermin D pore formation and pyroptosis, or mixed lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis. IL-1β and IL-1α can then bind and activate IL-1R on nearby cells, leading to downstream intracellular signalling, and the expression, processing and release of additional IL-1 proteins, ultimately causing a positive, autoinflammatory feedback loop, and recruitment of neutrophils and other inflammatory cells. The three approved IL-1-targeted biologic therapies prevent IL-1R activation (represented by T-ended arrows). Numerous other drugs, at various stages of development, target inflammasome components and upstream and downstream pathways (target symbols).

Fig. 3. Differential diagnostic considerations for monogenic disorders.

Certain clinical features are shared among autoinflammatory disorders and may be considered in the differential diagnosis of monogenic disorders directly driven by IL-1 (blue) or associated with IL-1 (orange). The lists shown here are not exhaustive and other disorders may be considered based on individual patient clinical presentations. For an overview of CARD14-mediated psoriasis, see ref.. AOSD, adult onset Still disease; CAPS, cryopyrin-associated periodic syndromes; CARD14-mediated psoriasis; CRMO, chronic recurrent multifocal osteomyelitis; DIRA, deficiency of IL-1 receptor antagonist; DITRA, deficiency of IL-36 receptor antagonist^,; FMF, familial Mediterranean fever; GPP, generalized pustular psoriasis; HA20, haploinsufficiency of A20 (ref.); HLH, hemophagocytic lymphohistiocytosis; MKD, mevalonate kinase deficiency; NLRC4, NLR family CARD domain containing 4 (ref.); NOCARH, neonatal-onset cytopenia with dyshaematopoiesis, autoinflammation, rash, and HLH; NOMID, neonatal-onset multisystem inflammatory disease; PAAND, pyrin-associated autoinflammation with neutrophilic dermatosis; PAPASH, pyogenic arthritis, acne, pyoderma gangrenosum, and suppurative hidradenitis; PASH, pyoderma gangrenosum, acne, suppurative hidradenitis; PASS, pyoderma gangrenosum, acne and suppurative hidradenitis; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, adenitis; PLAID, PLCγ2-associated antibody deficiency and immune dysregulation^,; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis; sJIA, systemic juvenile idiopathic arthritis; TRAPS, tumour necrosis factor receptor-associated periodic syndrome.