Arid5a makes the IL-17A/F–responsive pathway less arid

The proinflammatory cytokine interleukin-17A (IL-17A) stimulates the production of other cytokines and chemokines [for example, IL-6, IL-8, and G-CSF (granulocyte colony-stimulating factor)] from various nonhematopoietic cells (for example, epithelial cells, endothelial cells, and fibroblasts) and promotes the recruitment and activation of monocytes and neutrophils. The IL-17 family comprises five other members (IL-17B to IL-17F) (1). IL-17A and IL-17F, its closest relative, can homo- or heterodimerize. Because of their shared response pathway, overlapping roles, and common sources, we refer to these three dimers as IL-17A/F. The main source of IL-17A/F is a distinct lineage of CD4⁺ T_H17 (T helper 17) cells (2) but is also produced by γδ T cells, CD8⁺ T_C17 (T cytotoxic 17) cells, ILC3s (type 3 innate lymphoid cells), iNKT (invariant natural killer T) cells, and MAIT (mucosal-associated invariant T) cells (3). IL-17A/F signals through the IL-17 receptor A (IL-17RA) and IL-17RC subunits, which belong to the IL-17R family (including IL-17RB, IL-17RD, and IL-17RE). These receptors contain a conserved SEFIR (similar expression of fibroblast growth factor and IL-17R) domain. Although IL-17RA is ubiquitously expressed, IL-17RC expression is restricted to nonhematopoietic cells, mostly on fibroblasts, keratinocytes, endothelial cells, and epithelial cells (4).

The biological response downstream of IL-17RA/IL-17RC is mediated by the SEFIR-containing adaptor protein and E3 ubiquitin ligase nuclear factor κB (NF-κB) activator 1 (ACT1), which recruits and ubiquitylates tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), leading to the activation of NF-κB, CCAAT/enhancer binding protein (C/EBP), and MAPK (mitogen-activated protein kinase) signaling pathways. This ultimately leads to the production of cytokines and chemokines (for example, IL-6), antimicrobial peptides (for example, β-defensins), matrix metalloproteinases (for example, MMP-1), and transcription factors [for example, NF-κB inhibitor ζ (IκBζ)]. These IL-17A/F–dependent effects are mediated through at least two mechanisms. First, IL-17A/F augments target gene messenger RNA (mRNA) stabilization. Indeed, a number of IL-17A/F target genes contain adenylate-uridylate–rich elements or similar sequences in their 3′ untranslated regions (3′UTRs). The RNA binding protein (RBP) Hu-antigen R (HuR) and the adenosine 5′-triphosphate–dependent RNA helicase DD3X generally contribute to mRNA stabilization. Some of their targets are induced by mouse IL-17A/F, such as cytokine- or chemokine-encoding mRNAs (for example, Il6), or are negative regulators of the IL-17A/F pathway [for example, Zc3h12a, which encodes the endoribonuclease MCP-1 (monocyte chemoattractant protein-1)–induced protein 1 (MCPIP1)]. Second, IL-17A/F also increases the expression of the transcription factors IκBζ and C/EBPβ, which induce target gene expression and contribute to the synergistic effect of IL-17A/F, together with other stimuli (for example, TNF-α) (5).

How IL-17A/F promotes these activities remains largely unknown. In this issue of Science Signaling, Amatya et al. showed that the RBP Arid5a increased the response to IL-17A/F through multiple mechanisms (6). The authors found that Arid5a expression was increased in the tongue of mice orally infected with Candida albicans and in the ST2 mouse stromal cell line after treatment with IL-17A. The small interfering RNA–mediated knockdown of Arid5a in ST2 cells suppressed the IL-17A–dependent induction of IL-6, CXCL1, and CXCL5 mRNAs and proteins, whereas the expression of Csf2 and Ccl20 mRNAs was unaffected. The authors further showed that Arid5a interacted with TRAF2 to promote mRNA stabilization, as was previously shown for the RBP HuR. The binding of Arid5a to the 3′UTRs of Il6, Cxcl1, or Cxcl5 offsets the negative effect of MCPIP1, which binds to the same region, ultimately promoting their induction. In parallel, Arid5a also induced IL-17A–dependent target mRNAs indirectly, through the induction of IL-17–dependent transcription factors (for example, Lcn2). In that context, Arid5a enhanced both mRNA stability (by binding to 3′UTRs) and mRNA translation (probably by facilitating access of the translation initiation complex elF4G to target promoters), as was shown for Nfkbiz, or mRNA translation only, as was shown for Cebpb (Fig. 1).

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Understanding the biochemical pathways activated by IL-17A/F is medically relevant. Indeed, IL-17A/F contributes to the pathogenesis of autoinflammatory, autoimmune, and even malignant phenotypes in mice. Although a similar role for IL-17A/F has been suggested in humans, it has not been genetically proven. IL-17A/F may be involved in the development of conditions as diverse as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma. Antibodies targeting IL-17A (secukinumab and ixekizumab) or IL-17RA (brodalumab) can effectively treat plaque psoriasis. However, their effect on ankylosing spondylitis and psoriatic arthritis is less efficient and may even be deleterious in Crohn’s disease or other conditions. Mouse studies suggest that the protective role for IL-17A/F in maintaining intestinal barrier integrity predominates over its potential role in tissue damage during inflammatory bowel disease (7).

Mouse IL-17A/F plays a crucial role in protection at different anatomical sites against various pathogens, including viruses, bacteria, fungi, and parasites. In humans, the description of patients with inherited forms of isolated chronic mucocutaneous candidiasis (CMC) due to inborn errors of IL-17A/F–mediated immunity (autosomal-dominant IL-17F, autosomal-recessive IL-17RA, IL-17RC, and ACT1 deficiencies) indicates that IL-17A/F–mediated immunity plays a crucial role in mucocutaneous host defense against C. albicans (8, 9). Intriguingly, patients with IL-17RA and ACT1 deficiencies, but not IL-17F or IL-17RC deficiency, are also vulnerable to Staphylococcus aureus. None of the patients with any of these four deficiencies suffers from other unusually severe infections, suggesting that human IL-17A/F is largely redundant—even against invasive infections by Candida or Staphylococcus (8, 9). Consistently, some patients (2 to 4%) treated with anti–IL-17A or anti–IL-17RA antibodies develop mild mucosal candidiasis, whereas most patients do not, probably because the effect of the therapeutics may not be as strong as that of the genetic deficiency.

Arid5a is a unique RBP that binds to the 3′UTR of Il6 mRNA, which protects it from the endoribonuclease MCPIP1 and thereby stabilizes it. Accordingly, Arid5a-deficient mice have low concentrations of serum IL-6 upon exposure to lipopolysaccharide. Consistent with the work from Amatya et al., these mice do not develop some IL-17A/F–dependent autoimmune phenotypes (10). The discovery of Arid5a as a positive regulator of the IL-17A/F pathway poses exciting challenges. Are the IL-17A/F pathways controlling mucocutaneous immunity to C. albicans identical to those involved in autoinflammation or autoimmunity? Are Arid5a-deficient mice vulnerable to C. albicans? What controls the balance between positive (Arid5a) and negative (MCPIP1) signals downstream of IL-17RA/RC? Is Arid5a necessary in all or in only some of the IL-17A/F–responsive cells for appropriate responses? Does it control cellular responses to other IL-17 family cytokines? What makes Arid5a target specific mRNAs? What are the mechanisms controlling Arid5a expression? Importantly, does Arid5a operate in humans, too? If so, would loss-of-function variants of ARID5A underlie CMC and gain-of-function variants underlie inflammatory or autoimmune diseases?