Abstract
Fibrinogen-like protein 2 (Fgl2) is critical for immune regulation in the inflammatory state. Elevated Fgl2 levels are observed in patients with inflammatory bowel disease (IBD), but little is known about its functional significance. In this study, we sought to investigate the role of Fgl2 in the development of intestinal inflammation and colitis-associated colorectal cancer (CAC). Here, we report that Fgl2 deficiency increased susceptibility to dextran sodium sulfate-induced colitis and CAC in a mouse model. During colitis development, the expression of the membrane-bound and secreted forms of Fgl2 (mFgl2 and sFgl2, respectively) in the colon were increased and predominantly expressed by colonic macrophages. In addition, using bone marrow chimeric mice, we determined that Fgl2 function in colitis is strictly related to its expression in the hematopoietic cells. Loss of Fgl2 induced the polarization of M1, but suppressed that of M2 both in vivo and in vitro, independent of intestinal inflammation. Thus, Fgl2 suppresses intestinal inflammation and CAC development through its role in macrophage polarization and may serve as a therapeutic target in inflammatory diseases, including IBD.
Highlights
The maintenance of intestinal homeostasis requires a balance of immune tolerance and effector functions
We noted a gradual upregulation of sFgl2 expression along with colitis progression (Figure 1B; Figures S1A,B in Supplementary Material). sFgl2 is mainly secreted by T cells, activated Tregs [23]; whether other types of cells secrete sFgl2 under colitis condition remains unclear
We sorted colonic epithelial cells (CD45− EpCAM+), Tregs (CD4+ CD25high), macrophages (CD11b+ F4/80+), dendritic cells (DCs) (CD11b+ F4/80− CD11c+), and neutrophils (CD11bhigh Gr-1high) on day 7 after dextran sodium sulfate (DSS) induction (Figure S1C in Supplementary Material) and analyzed sFgl2 production by Enzyme-Linked Immunosorbent Assay (ELISA). sFgl2 was detected in Tregs and DCs but not in epithelial cells or neutrophils
Summary
The maintenance of intestinal homeostasis requires a balance of immune tolerance and effector functions. Disruption of this homeostasis results in pathologies such as inflammatory bowel disease (IBD), of which there are two major clinical forms: ulcerative colitis and Crohn’s disease. There are no effective cures for IBD [1, 2]. Long-term intestinal inflammation is a key risk factor for colitis-associated colorectal cancer (CAC) [3]. IBD is characterized by abnormalities in intestinal immunity, the pro-inflammatory response in the gut [4, 5].
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