The role of CD4+ T cells specifically, Th17 has been well documented in RA pathogenesis. Here we focus on the critical role of cytokines IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL. Neutralizing IL-21 or IL- 23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-α, IFN-γ and IL- 17 and RANKL expression in RA CD4+ T cells. Our ex vivo human Th17 studies also validated the above findings and we hypothesize a common pathway responsible for regulation of inflammatory cytokines and RANKL expression. Subsequent dissection of the signalling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of augmenting inflammatory cytokines and RANKL production. Altogether, these findings identify IL-21/23 axis in RA CD4+ T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher osteoclastogenesis and provide critical targets in their downstream signalling for therapeutic approaches.

The authors have declared no competing interest.

This study was supported by the Institute of Life Sciences, Bhubaneswar, Department of Biotechnology (DBT), Government of India. GB and SKS were funded by CSIR fellowship, SS by DBT and RJ by Institutional fellowships respectively

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