Complex inflammatory signalling cascades define the response to tissue injury but also control development and homeostasis, limiting the potential for these pathways to be targeted therapeutically. Primary cilia are subcellular regulators of cellular signalling, controlling how signalling is organized, encoded and, in some instances, driving or influencing pathogenesis. Our previous research revealed that disruption of ciliary intraflagellar transport (IFT), altered the cell response to IL-1β, supporting a putative link emerging between cilia and inflammation. Here, we show that IFT88 depletion affects specific cytokine-regulated behaviours, changing cytosolic NFB translocation dynamics but leaving MAPK signalling unaffected. RNA-seq analysis indicates that IFT88 regulates one third of the genome-wide targets, including the pro-inflammatory genes Nos2, Il6 and Tnf. Through microscopy, we find altered NFB dynamics are independent of assembly of a ciliary axoneme. Indeed, depletion of IFT88 inhibits inflammatory responses in the non-ciliated macrophage. We propose that ciliary proteins, including IFT88, KIF3A, TTBK2 and NPHP4, act outside of the ciliary axoneme to tune cytoplasmic NFB signalling and specify the downstream cell response. This is thus a non-canonical function for ciliary proteins in shaping cellular inflammation.

This article has an associated First Person interview with the first author of the paper.

复杂的炎症信号级联反应定义了对组织损伤的反应，但也控制了发育和体内稳态，从而限制了这些途径在治疗上的针对性。原发纤毛是细胞信号传导的亚细胞调节剂，控制信号传导的组织方式，编码方式，并在某些情况下控制或影响发病机理。我们先前的研究表明，破坏睫状鞭毛内运输（IFT）会改变细胞对IL-1β的反应，从而支持纤毛和炎症之间出现一种推测的联系。在这里，我们表明IFT88耗竭影响特定的细胞因子调节的行为，改变细胞质NFB易位动力学，但不影响MAPK信号传导。RNA-seq分析表明IFT88调节了全基因组靶标的三分之一，包括促炎基因Nos2，Il6和Tnf。通过显微镜，我们发现改变的NFB动力学独立于睫状轴突的组装。实际上，IFT88的消耗会抑制非纤毛巨噬细胞的炎症反应。我们建议，包括IFT88，KIF3A，TTBK2和NPHP4的纤毛蛋白在纤毛轴突之外起作用，以调节细胞质NFB信号传导并指定下游细胞应答。因此，这是睫状蛋白在塑造细胞炎症中的非典型功能。

本文与论文的第一作者进行了第一人称访谈。