ZC3H12C expression in dendritic cells is necessary to prevent lymphadenopathy of skin‐draining lymph nodes

Abstract

The role of RNA-binding proteins of the CCCH-containing family in regulating proinflammatory cytokine production and inflammation is increasingly recognized. We have identified ZC3H12C (Regnase-3) as a potential post-transcriptional regulator of tumor necrosis factor expression and have investigated its role in vivo by generating Zc3h12c-deficient mice that express green fluorescent protein instead of ZC3H12C. Zc3h12c-deficient mice develop hypertrophic lymph nodes. In the immune system, ZC3H12C expression is mostly restricted to the dendritic cell (DC) populations, and we show that DC-restricted ZC3H12C depletion is sufficient to cause lymphadenopathy. ZC3H12C can regulate Tnf messenger RNA stability via its RNase activity in vitro, and we confirmed the role of Tnf in the development of lymphadenopathy. Finally, we found that loss of ZC3H12C did not impact the outcome of skin inflammation in the imiquimod-induced murine model of psoriasis, despite Zc3h12c being identified as a risk factor for psoriasis susceptibility in several genome-wide association studies. Our data suggest a role for ZC3H12C in DC-driven skin homeostasis.

Immunology & Cell Biology's Top 10 original research articles 2021–2022

“…and Langerhans cells) in the lymph nodes, and when genetically deleted from mice, the absence of this RNAbinding protein led to lymphadenopathy. 4 Interestingly, deficiency in TNF-a reversed the effect suggesting a regulatory role for ZC3H12C on TNF-a especially during skin homeostasis. 4 Curson et al 5 investigated a newly identified variant of Scimp, an adapter in TLR signaling, to discover that its unique signaling and localization supported distinct and diverse functions through this key innate signaling pathway in macrophages.…”

“…• Clayer et al 4 ZC3H12C expression in dendritic cells is necessary to prevent lymphadenopathy of skin-draining lymph nodes.…”

“…explored the expression and function of the post‐transcriptional regulator, ZC3H12C, which has been shown to negatively regulate pro‐inflammatory cytokine responses. They detected the highest expression of ZC3H12C in DC populations (migratory cDC1 and 2 and Langerhans cells) in the lymph nodes, and when genetically deleted from mice, the absence of this RNA‐binding protein led to lymphadenopathy 4 . Interestingly, deficiency in TNF‐α reversed the effect suggesting a regulatory role for ZC3H12C on TNF‐α especially during skin homeostasis 4 .…”

“…Tolerance induction by liposomes targeting a single CD8 epitope IGRP 206‐214 in a model of type 1 diabetes is impeded by co‐targeting a CD4 + islet epitope. Vanderven et al 3 . Poor protective potential of influenza nucleoprotein antibodies despite wide prevalence. Clayer et al 4 . ZC3H12C expression in dendritic cells is necessary to prevent lymphadenopathy of skin‐draining lymph nodes. Curson et al 5 .…”

“…turned their focus onto myeloid cells to understand and characterize the signaling and localization of dendritic cells (DC) and macrophages during inflammation and homeostasis. The article by Clayer et al 4 . explored the expression and function of the post‐transcriptional regulator, ZC3H12C, which has been shown to negatively regulate pro‐inflammatory cytokine responses.…”