Chronic kidney disease (CKD) is a major worldwide public health concern [1], [2]. Following kidney damage, inflammation and fibrosis occur to resolve the tissue injury and maintain tissue homeostasis [3]. However, when kidney function declines to some extent as a result of kidney injury or certain diseases, CKD can develop, and its pathology progresses irreversibly, irrespective of the primary disease; as such, it is considered a final common pathway [4], [5]. Renal interstitial fibrosis is a classical hallmark of the final common pathway, and the degree of pathological progression in the renal interstitium is correlated with kidney function and prognosis [6]. Renal injuries and diseases enable the infiltration of innate immune cells into the renal interstitium, and these cells play roles in the initial steps of renal inflammation and fibrosis, thereby contributing to CKD progression [7], [8]. Indeed, many reports have revealed that renal macrophages are involved in the onset and progression of renal fibrosis [9], [10], [11], [12]; however, whether other innate immune cells contribute to this pathology remains unclear. Therefore, it is necessary to identify the responsible innate immune cells to develop novel therapeutic agents to overcome renal fibrosis and CKD.

Innate lymphoid cells (ILCs) are capable of activation independent of antigen presentation, and they are subdivided into three groups (ILC1s, ILC2s, ILC3s) on the basis of function and transcriptional factors, similar to helper T cell subsets [13]. Many reports have described ILC-regulating molecules, including cytokines, peptides, and hormones [14]. ILC2s respond to alarmins such as IL-33, which is released from damaged cells, leading the cells to rapidly produce large amounts of type 2 cytokines. ILC2s are abundant in the lungs, intestines, and skin, and they are also resident in kidney, where they protect against renal injury and diseases [15], [16], [17]. We previously demonstrated that UUO-induced renal fibrosis was attenuated by the IL-33/ILC2 axis [18]. Therefore, renal ILC2s are involved in renal fibrosis and represent a potential therapeutic target for fibrosis; however, the mechanisms by which ILC2s attenuate renal fibrosis are not clearly understood.

In this study, we demonstrated that numbers of kidney-resident ILC2s are decreased in CKD kidney and that ILC2 expansion induced by exogenous IL-33 suppresses renal fibrosis associated with CKD progression. The CKD tissue environment exhibited altered GATA3 expression and ILC2 response to IL-33, and the capacity of kidney ILC2s to produce IL-13 was enhanced, whereas production of IL-5 was impaired when cells were stimulated with IL-33. Kidney ILC2s directly affected renal fibroblasts in a cell contact–dependent and/or –independent manner. These findings suggest that kidney ILC2s play a protective role in renal fibrosis associated with CKD. Furthermore, transition of renal fibroblasts to myofibroblasts was suppressed by ILC2s, which could be targeted to potentially alleviate CKD progression.