DICER1: A Key Player in Rheumatoid Arthritis, at the Crossroads of Cellular Stress, Innate Immunity, and Chronic Inflammation in Aging

Abstract

Loss-of-function or knockout mouse models have established a fundamental role for the RNAse III enzyme DICER1 in development and tissue morphogenesis and/or homeostasis. These functions are currently assumed to result mainly from the DICER1-dependent biogenesis of microRNAs which exhibit important gene expression regulatory properties. However, non-canonical DICER1 functions have recently emerged. These include interaction with the DNA damage response (DDR) pathway and the processing of cytotoxic non-coding RNAs, suggesting that DICER1 might also participate in the regulation of major cellular processes through miRNA-independent mechanisms. Recent findings indicated that reduced Dicer1 expression, which correlates with worsened symptoms in mouse models of joint inflammation, is also noted in fibroblast-like synoviocytes (FLS) harvested from rheumatoid arthritis (RA) patients, as opposed to FLS cultured from biopsies of osteoarthritic patients. In addition, low DICER1 levels are associated with the establishment of cellular stress and its associated responses, such as cellular senescence. Senescent and/or stressed cells are associated with an inflammatory secretome (cytokines and chemokines), as well as with "find-me" and "eat-me" signals which will attract and activate the innate immune compartment (NK cells, macrophages, and neutrophils) to be eliminated. Failure of this immunosurveillance mechanism and improper restauration of homeostasis could lead to the establishment of a systemic and chronic inflammatory state. In this review, we suggest that reduced DICER1 expression contributes to a vicious cycle during which accumulating inflammation and premature senescence, combined to inadequate innate immunity responses, creates the appropriate conditions for the initiation and/or progression of autoimmune-autoinflammatory diseases, such as RA.

Keywords: Dicer1; ageing; inflammation; rheumatoid arthritis; senescence.

Figure 1

Canonical and non-canonical functions of DICER1 in the nucleus and the cytosol. The canonical function of DICER1 leads to microRNA maturation in the cytoplasm. Others functions are considered non-canonical.

Figure 2

DICER1 functions at the crossroads of inflammation, senescence and aging. Examples of microRNAs involved in both rheumatoid arthritis (RA) and inflammation (miR-155 and -146a), RA and senescence (miR-34a) or RA and stress (miR-124a) are shown. The model illustrates how an initial trigger (e.g., a viral infection) might initiate a vicious circle (see text).