Developmental ANGPTL4 deficiency protects mice from colitis and tumors

A novel study using a mouse model has found that the absence of the angiopoietin-like 4 (ANGPTL4) protein during development triggers a long-lasting reprogramming of the immune system that protects against intestinal inflammation. The findings from the study in The American Journal of Pathology, published by Elsevier, may have important implications for identifying molecular or cellular signatures that predict disease susceptibility, and for developing therapeutic strategies that enhance protective immune programs in inflammatory bowel disease and inflammation-driven colorectal cancer.

ANGPTL4 is a secreted glycoprotein primarily recognized for its pivotal role in lipid metabolism. Beyond its metabolic functions, ANGPTL4 is important for tissue stability and health (homeostasis) and has been implicated in various disease processes including cancer, wound healing, pulmonary inflammation, atherosclerosis, and notably, intestinal homeostasis.

The intestine is an important organ for nutrient absorption and immune defense, which is continuously exposed to a multitude of antigens and microbes. Disruptions in intestinal homeostasis can result in pathologic outcomes, such as inflammatory bowel disease and colitis, with prolonged inflammation increasing the risk of colorectal cancer.

Previous research on Angptl4 knockout mice (with the gene "switched off") uncovered striking outcomes; while some pups died within the first two weeks of life due to impaired intestinal lymphatic development and severe intestinal inflammation, survivors developed normally without obvious lymphatic defects.

While prior studies focused mainly on the mice that developed fatal early-life complications, this study examined the long-term health of surviving Angptl4 knockout mice.

"We hypothesized that the surviving Angptl4 knockout mice might undergo developmental adaptation that enables them to overcome those early intestinal challenges," says co-lead investigator Hoon-Ki Sung, MD, PhD, The Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada. "This made us wonder how these surviving knockout mice respond later in life when challenged with intestinal inflammation, and what the long-term consequences of Angptl4 deficiency in inflammatory settings are."

Unexpectedly, these mice were strongly protected against both intestinal inflammation and inflammation-driven colon tumors compared with normal, wild-type controls. This protection was associated with a shift in macrophage (a type of immune cell) behavior toward an alternatively activated state, suggesting that altered immune responses contribute to reduced disease severity and tumor formation.

A major novel insight from our study is that intestinal inflammation experienced during development can shape long-term immune programming, resulting in increased resistance to recurrent inflammatory challenges later in life. Understanding how early-life inflammatory events 'train' or reprogram intestinal immune responses may reveal new mechanisms by which the body prepares for future inflammatory insults."

Joe Eun Son, PhD, co-lead investigator, Department of Advanced BioConvergence, Kyungpook National University Daegu, Republic of Korea

To evaluate the clinical relevance in human colorectal cancer, The Cancer Genome Atlas Colorectal Adenocarcinoma data set was analyzed, showing that low ANGPTL4 expression levels correlated with lower inflammatory levels and improved survival rates in human colorectal adenocarcinoma.

These findings present a previously unrecognized impact of Angptl4 deficiency in intestinal pathogenesis and support the concept of trained immunity (epigenetic programming), in which early-life exposures can induce long-lasting reprogramming of the innate immune system.

"Our study highlights the significance of ANGPTL4 as a prognostic biomarker for bowel inflammation and colorectal cancer. Understanding the distinct roles of ANGPTL4 in different tissues will be crucial for developing targeted therapies that maximize benefits while minimizing adverse effects," concludes Dr. Son.