Divergent Roles for the IL-1 Family in Gastrointestinal Homeostasis and Inflammation

Abstract

Inflammatory disorders of the gastro-intestinal tract are a major cause of morbidity and significant burden from a health and economic perspective in industrialized countries. While the incidence of such conditions has a strong environmental component, in particular dietary composition, epidemiological studies have identified specific hereditary mutations which result in disequilibrium between pro- and anti-inflammatory factors. The IL-1 super-family of cytokines and receptors is highly pleiotropic and plays a fundamental role in the pathogenesis of several auto-inflammatory conditions including rheumatoid arthritis, multiple sclerosis and psoriasis. However, the role of this super-family in the etiology of inflammatory bowel diseases remains incompletely resolved despite extensive research. Herein, we highlight the currently accepted paradigms as they pertain to specific IL-1 family members and focus on some recently described non-classical roles for these pathways in the gastrointestinal tract. Finally, we address some of the shortcomings and sources of variance in the field which to date have yielded several conflicting results from similar studies and discuss the potential effect of these factors on data interpretation.

Keywords: cytokine; gastrointestinal; inflammation immunomodulation; inflammatory bowel conditions; interleukin-1.

Figure 1

Diagrammatic representation of tolerogenic mechanisms in the gastrointestinal tract. Homeostasis at the gastrointestinal mucosa involves several specialized immune cells and cross-talk with symbiotic microbes in the lumen. The first line of defense is provided by antibodies in the gut lumen, which are transported across the epithelial barrier via the pIgR, in conjunction with IEC-derived AMPs, production of which is stimulated by IEL or ILC-derived IL-22. Beneath the epithelial layer, the intestinal lamina propria is home to mononuclear phagocytes which can capture antigen either directly from the lumen via trans-epithelial extension of dendrites or through M cell passages. These MNPs can in turn pass antigenic material to migratory CD103⁺ DCs which favor a tolerogenic immune response through their ability to metabolize vitamin A into retinoic acid and activate latent TGFβ, both of which are involved in the differentiation of T_REGS and IgA class switch recombination in B cells. T_REGS and IgA-secreting plasma cells play fundamental roles in remaining tolerant to innocuous antigens from diet and the microbiota and dysregulated responses in either of these factors significantly enhances susceptibility to enteric inflammatory disorders.

Figure 2

Primary structures of IL-1 family cytokines. Diagrammatic representation of the primary structures of well characterized cytokines belonging to the IL-1 superfamily. While all contain consensus cleavage sites for caspases and/or inflammatory proteases, IL-1α and IL-33 also contain nuclear localization sequences in their N-terminal domains enabling them to traffic to the nucleus from where they can regulate inflammatory gene transcription. Activation of these cytokines via post-translational cleavage events has been extensively reviewed elsewhere (38).

Figure 3

IL-1 family receptors and negative regulators. Receptors of the IL-1 family bear close resemblance to TLRs in that they consist of an extracellular ligand-binding domain, a transmembrane helix and an intracellular TIR domain which mediates MyD88-dependent signal transduction. Due to the highly pleiotropic nature of IL-1 family cytokines, several natural antagonists and decoy receptors have been identified which ensure tight regulation of their functions. These inhibitory molecules can target the receptors themselves, as is the case for IL-1Ra and IL36Ra, or the active cytokines to prevent them from binding to their cognate receptors. Examples of the later include IL-18BP, as well as soluble and membrane-bound IL-1RII and soluble ST2. Finally, SIGIRR (TIR8) acts as an inhibitory receptor by sequestering intracellular kinases required for signaling via engaged IL-1 family receptors.

Figure 4

Schematic of the NLRP3 inflammasome complex. The prototypical inflammasome-forming NLR consisting of the sensory component NLRP3 bound via PRYIN domain interactions with the adaptor protein ASC, which in turn associates with caspase-1 via their respective CARD domains. An initial stimulus, such as a TLR ligand, primes the inflammasome via the ligand sensing LRR domain, thereby initiating oligomerization of NACHT domains and activation of the inflammasome which results in the production of cytokines including pro-IL-1β and pro-IL-18. A subsequent second signal, such as potassium ion efflux, induces the autocatalysis and activation of caspase-1. This autocatalytic event enables the enzyme to cleave its substrates which include both pro-IL-1β and pro-IL-18 as well as the pore-forming protein gasdermin D. Once released into the extracellular space, these bioactive cytokines can go on to signal in an auto- or paracrine manner.