SARI attenuates colon inflammation by promoting STAT1 degradation in intestinal epithelial cells

Abstract

SARI functions as a suppressor of colon cancer and predicts survival of colon cancer patients, but its role in regulating colitis has not been characterized. Here we show that SARI −/− mice were highly susceptible to colitis, which was associated with enhanced macrophage infiltration and inflammatory cytokine production. Bone marrow reconstitution experiments demonstrated that disease susceptibility was not dependent on the deficiency of SARI in the immune compartment but on the protective role of SARI in the intestinal epithelial cells (IECs). Furthermore, SARI deficiency enhanced Chemokine (C-C motif) Ligand 2 (CCL2) production and knockout of CCR2 blocks the promoting role of SARI deficiency on colitis. Mechanistically, SARI directly targets and promotes signal transducer and activator of transcription 1 (STAT1) degradation in IECs, followed by persistent inactivation of the STAT1/CCL2 transcription complex. In summary, SARI attenuated colitis in mice by impairing colitis-dependent STAT1/CCL2 transcriptional activation in IECs and macrophages recruitment in colon tissue.

SARI suppresses colitis‐associated cancer development by maintaining MCP‐1‐mediated tumour‐associated macrophage recruitment

“…According to the present findings and our previous study, 18 we hypothesize that SARI impairs CAC through attenuating colitis by directly targeting and promoting protease-dependent degradation of STAT1 and the transcriptional activity of STAT1/MCP-1 (Figure 8).…”

“…CCR2 knockout blocks the SARI deficiency‐promoted tumorigenesis. Furthermore, STAT1 was also proved as the direct target of SARI in colon cancer cells, evidenced by Co‐IP and IF staining, as indicated in intestinal epithelial cells . Other transcriptional regulation factors of MCP‐1, including NF‐κB and STAT3, were up‐regulated in colon tissues of SARI −/− mice in CAC, but demonstrated not to be the direct target of SARI in colon cancer cells.…”

“…Furthermore, STAT1 was also proved as the direct target of SARI in colon cancer cells, evidenced by Co-IP and IF staining, as indicated in intestinal epithelial cells. 18 Other transcriptional regulation factors of MCP-1, including NF-κB 30,31 and STAT3, 32,33 were up-regulated in colon tissues of SARI −/− mice in CAC, but demonstrated not to be the direct target of SARI in colon cancer cells. The inverse correlation between SARI and p-STAT1 was also observed in colon malignant tissues of patients, whereas SARI mRNA expression was positively correlated with STAT1 mRNA expression.…”

SARI prevents ocular angiogenesis and inflammation in mice

“…Neutrophils and monocytes/macrophages were seen to infiltrate extravascular uveal tissue in LPS‐treated eyes and reached all the structures of interest (ciliary body, anterior, posterior and vitreous chambers, and retina). SARI deficiency caused significant increases of this effect . Conversely, the eyes in all PBS‐injected mice showed very minimal inflammatory changes with an absence of inflammatory cell infiltration in the anterior chamber and posterior segment (Figure 5A & C).…”

“…Likewise, a significant growth (82.5%) was also noted in the retina and vitreous chamber in EIU‐SARI −/− group vs. EIU‐SARI WT (Figure 5D). According to the regulation of CCL 2‐positive inflammatory cells infiltration in colon by SARI, we further determined the expression of CCL 2 in extravascular uveal tissue. Our results suggested that SARI deficiency promoted the expression of CCL 2 in EIU model (Figure 5E & F), which indicated that more CCL 2‐positive cells infiltrated the extravascular uveal tissue.…”