ELMO1 ameliorates intestinal epithelial cellular senescence via SIRT1/p65 signaling in inflammatory bowel disease-related fibrosis

Junguo Chen; Guanman Li; Xiaowen He; Xijie Chen; Zexian Chen; Danling Liu; Shuang Guo; Tianze Huang; Yanyun Lin; Ping Lan; Lei Lian; Xiaosheng He

doi:10.1093/gastro/goae045

ELMO1 ameliorates intestinal epithelial cellular senescence via SIRT1/p65 signaling in inflammatory bowel disease-related fibrosis

Gastroenterol Rep (Oxf). 2024 May 14:12:goae045. doi: 10.1093/gastro/goae045. eCollection 2024.

Authors

Junguo Chen^{1

2

3

4}, Guanman Li^{1

2

3

5}, Xiaowen He¹, Xijie Chen^{1

6}, Zexian Chen¹, Danling Liu¹, Shuang Guo¹, Tianze Huang¹, Yanyun Lin¹, Ping Lan^{1

2

3}, Lei Lian⁶, Xiaosheng He^{1

2

3}

Affiliations

¹ Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
² Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
³ Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
⁴ Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
⁵ School of Medicine (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, P. R. China.
⁶ Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.

Abstract

Background: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD), which still lacks of reliable markers and therapeutic options. Cellular senescence has been considered an important mechanism of intestinal fibrosis, but the underlying molecular link remains elusive.

Methods: Tissues were stained using α-smooth muscle actin (α-SMA), fibronectin, and collagen I as markers of myofibroblastic differentiation. Cellular senescence was confirmed through Lamin B1 staining, senescence-associated β-galactosidase staining, and the expression of senescence-associated secretory phenotype (SASP) factors. We explored the relationship between senescence of intestinal epithelial cells (IECs) and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. The effects of irisin on cellular senescence and fibrosis were determined.

Results: Here, we identify engulfment and cell motility protein 1 (ELMO1) as a novel biomarker for intestinal cellular senescence and fibrosis. In fibrostrictured tissues from patients and murine models with IBD, significantly high levels of cellular senescence score and factors were noted, which positively correlated with the fibrotic regulator fibronectin. Senescent IECs, not fibroblast itself, released SASP factors to regulate fibroblast activation. Prolonging exposure to severe and persistent injurious stimuli decreased ELMO1 expression, which dampened SIRT1 deacetylase activity, enhanced NF-κB (p65) acetylation, and thereby accelerated cellular senescence. Deletion of ELMO1 led to senescent IECs accumulation and triggered premature fibrosis in murine colitis. Furthermore, irisin, inhibiting the degradation of ELMO1, could downregulate p65 acetylation, reduce IECs senescence, and prevent incipient intestinal fibrosis in murine colitis models.

Conclusions: This study reveals ELMO1 downregulation is an early symbol of intestinal senescence and fibrosis, and the altered ELMO1-SIRT1-p65 pathway plays an important role in intestinal cellular senescence and IBD-related fibrosis.

Keywords: ELMO1; IBD-related fibrosis; exercise hormone; irisin; p65 acetylation; senescence.