Identification of Functional Roles for Both IL-17RB and IL-17RA in Mediating IL-25-Induced Activities

Abstract

IL-25 (IL-17E) is a unique IL-17 family ligand that promotes Th2-skewed inflammatory responses. Intranasal administration of IL-25 into naive mice induces pulmonary inflammation similar to that seen in patients with allergic asthma, including increases in bronchoalveolar lavage fluid eosinophils, bronchoalveolar lavage fluid IL-5 and IL-13 concentrations, goblet cell hyperplasia, and increased airway hyperresponsiveness. IL-25 has been reported to bind and signal through IL-17RB (IL-17BR, IL-17Rh1). It has been demonstrated recently that IL-17A signals through a heteromeric receptor composed of IL-17RA and IL-17RC. We sought to determine whether other IL-17 family ligands also utilize heteromeric receptor complexes. The required receptor subunits for IL-25 biological activities were investigated in vitro and in vivo using a combination of knockout (KO) mice and antagonistic Abs. Unlike wild-type mice, cultured splenocytes from either IL-17RB KO or IL-17RA KO mice did not produce IL-5 or IL-13 in response to IL-25 stimulation, and both IL-17RB KO and IL-17RA KO mice did not respond to intranasal administration of IL-25. Furthermore, treatment with antagonistic mAbs to either IL-17RB or IL-17RA completely blocked IL-25-induced pulmonary inflammation and airway hyperresponsiveness in naive BALB/c mice, similar to the effects of an antagonistic Ab to IL-25. Finally, a blocking Ab to human IL-17RA prevented IL-25 activity in a primary human cell-based assay. These data demonstrate for the first time that IL-25-mediated activities require both IL-17RB and IL-17RA and provide another example of an IL-17 family ligand that utilizes a heteromeric receptor complex.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…To date, IL-17A and IL-17F have been shown to form either homodimers or heterodimers that can bind to the IL-17RA and IL-17RC receptor complex to activate downstream signaling cascades, whereas IL-17E is believed to signal though the IL-17RA and IL-17RB receptor complex to activate its downstream pathways. 9,[21][22][23][24] At present, the IL-17RA and IL-17RE heterodimer is considered the functional receptor for IL-17C. [25][26][27] IL-17RB has also been suggested to be a receptor for IL-17B; 28,29 however, evidence from genetic deficiency experiments is lacking for this receptor and ligand combination.…”

“…Indeed, both IL-17RA and IL-17RB are functionally required for its signaling. 24 Genetic alteration of either IL-17RA or IL-17RB abolishes IL-17E-mediated signaling and the downstream response. 24 Unlike IL-17, which targets a broad range of cell types, IL-17E prefers to target hematopoietic cells such as Th2, Th9 or NKT cells to induce the production of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13.…”

“…24 Genetic alteration of either IL-17RA or IL-17RB abolishes IL-17E-mediated signaling and the downstream response. 24 Unlike IL-17, which targets a broad range of cell types, IL-17E prefers to target hematopoietic cells such as Th2, Th9 or NKT cells to induce the production of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13. 9 In addition to T cells, IL-17RB is also expressed on monocytes, type 2 cytokine-producing myeloid (T2M) cells and several populations of type 2 innate lymphoid cells including nuocytes, non-T/non-B (NBNT) cells, multipotent progenitor type2 (MMP type2 ) cells and innate type2 helper (ih2) cells.…”

Interleukin-17 cytokine signalling in patients with asthma

“…Tentatively, IL-25, with its proven link to the mobilisation of eosinophils rather than neutrophils, and its unique signalling via the IL-17receptor A/receptor B complex, remains of interest for further studies in patients with asthma [77,78]. Based upon the few and relatively small studies conducted to date, it is possible, but not proven, that IL-25 is involved in the pathogenesis of certain phenotypes of asthma.…”

A Focus on IL-17 Targeting Treatments in Psoriasis

“…At a lesser degree, IL-17RA also binds IL-17F, and IL-17A/IL-17F and seems to be critical for their transduction [24] . A recent study suggests that IL-17RA might also be a part of the IL-25 receptor complex since Il17ra -/-miceare refractory to the effects of IL-25.IL-17RA is used by multiple cytokines indicating that it could be analogous to common cytokine receptor subunits such as gp130 in the IL-6 family [25] . Downstream, the transcription factor nuclear factor-kB (NFkB) is then activated and favours pro-inflammatory gene expression [26] .…”