Nuclear IL-33 restrains the early conversion of fibroblasts to an extracellular matrix-secreting phenotype

Abstract

Interleukin (IL)-33 is a cytokine that appears to mediate fibrosis by signaling via its receptor ST2 (IL-33R/IL1RL1). It is also, however, a protein that after synthesis is sorted to the cell nucleus, where it appears to affect chromatin folding. Here we describe a novel role for nuclear IL-33 in regulating the fibroblast phenotype in murine kidney fibrosis driven by unilateral ureteral obstruction. Transcriptional profiling of IL-33-deficient kidneys 24 h after ligation revealed enhanced expression of fibrogenic genes and enrichment of gene sets involved in extracellular matrix formation and remodeling. These changes relied on intracellular effects of IL-33, because they were not reproduced by treatment with a neutralizing antibody to IL-33 that prevents IL-33R/ST2L receptor signaling nor were they observed in IL-33R/ST2-deficient kidneys. To further explore the intracellular function of IL-33, we established transcription profiles of human fibroblasts, observing that knockdown of IL-33 skewed the transcription profile from an inflammatory towards a myofibroblast phenotype, reflected in higher levels of COL3A1, COL5A1 and transgelin protein, as well as lower expression levels of IL6, CXCL8, CLL7 and CCL8. In conclusion, our findings suggest that nuclear IL-33 in fibroblasts dampens the initial profibrotic response until persistent stimuli, as enforced by UUO, can override this protective mechanism.

Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer

“…Accumulating evidence indicates that the intracellular forms of some secreted proteins, such as IL-33, IL-37, and MIF (macrophage migration inhibitory factor), are involved in the biological processes via interacting with cytoplasmic proteins. 39 – 41 Also, CYTL1 has received considerable attention as a secreted cytokine-like protein. This study demonstrates that the intracellular form of CYTL1 has a distinctive function from the secreted form.…”

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

“…In fact, there are many publications showing that the IL-33/ST2 pathway exacerbates the structural and functional damage of the kidneys in CKD (Table 2). Specifically, in studies of UUO model that is classical renal fibrosis model (Chevalier et al, 2009;Martínez-Klimova et al, 2019), IL-33 inhibited fibrosis in the early stages (Gatti et al, 2021). However, continuous stimulation resulted in significant upregulation of the IL-33/ST2 pathway (Chen et al, 2016;Li et al, 2019b;Gatti et al, 2021).…”

“…Specifically, in studies of UUO model that is classical renal fibrosis model (Chevalier et al, 2009;Martínez-Klimova et al, 2019), IL-33 inhibited fibrosis in the early stages (Gatti et al, 2021). However, continuous stimulation resulted in significant upregulation of the IL-33/ST2 pathway (Chen et al, 2016;Li et al, 2019b;Gatti et al, 2021). In a word, the progression of renal disease is associated with the sustained activation of IL-33/ST2.…”

Highland Barley Tea Polyphenols Extract Alleviates Skeletal Muscle Fibrosis in Mice by Reducing Oxidative Stress, Inflammation, and Cell Senescence

“…Oxidative stress, TGF-β , SA-β-gal, and inflammatory factors contribute to aging and fibrosis. , Aging leads to increased oxidative stress levels and a strong association between inflammation . One study suggests that inflammation positively correlates with fibrosis and is the main driver of fibrosis . At the onset of inflammation, TGF-β activates inflammatory cytokines and promotes fibrosis in a positive feedback loop .…”