Reg3b, a member of the Reg3 protein family, is an antimicrobial peptide. It contains a C-type lectin domain involved in carbohydrate binding and is expressed by intestinal epithelial cells. Reg3b has pleiotropic functions such as tissue repair, and it is associated with various biological processes like maintaining intestinal-barrier integrity and modulating immune responses [4,6]. Genetic mouse models have been crucial for studying its functions.

In gene knockout studies, Reg3b-/-mice showed increased susceptibility to intestinal translocation of the gram-negative bacterium Salmonella enteritidis, indicating its protective role against this pathogen [4]. In colitis models, deletion of Reg3b in transgenic mice exacerbated embryonic lethality in those with severe ileitis, and dextran sulfate sodium-induced colitis was more severe in Reg3b-/-mice compared to wild-type, suggesting its role in attenuating colitis and ileitis [6]. In non-alcoholic steatohepatitis (NASH) research, Reg3b deficiency protected against glucose intolerance, but liver disease, bacterial translocation, and plasma endotoxin levels were similar to wild-type littermates [5]. Also, in the context of fructose-induced liver steatosis, expression of Reg3b counteracted fructose-induced intestinal-barrier deterioration [1]. In pancreatic cancer-related studies, exogenous Reg3b induced acinar to ductal metaplasia (ADM) in murine acinar cells, and targeting it could potentially prevent early pancreatic ductal adenocarcinoma (PDAC) carcinogenesis [2]. In colitis-associated cancer (CAC) mouse models, disruption of genes that suppress Reg3b expression led to reduced polyp formation and less aggressive adenomas, and REG3B was shown to negatively regulate cytokine-induced activation of STAT3 in colon epithelial cells [3].

In conclusion, Reg3b plays essential roles in maintaining intestinal health, influencing glucose metabolism, and in the pathogenesis of various diseases including NASH, colitis, and pancreatic cancer. The use of Reg3b KO mouse models has significantly enhanced our understanding of its functions in these disease areas, providing insights that may guide future therapeutic strategies.

References:

1. Todoric, Jelena, Di Caro, Giuseppe, Reibe, Saskia, Febbraio, Mark A, Karin, Michael. 2020. Fructose stimulated de novo lipogenesis is promoted by inflammation. In Nature metabolism, 2, 1034-1045. doi:10.1038/s42255-020-0261-2. https://pubmed.ncbi.nlm.nih.gov/32839596/

2. Zhang, Huairong, Corredor, Andrea Liliam Gomez, Messina-Pacheco, Julia, Liu, Jun-Li, Gao, Zu-Hua. 2021. REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. In Communications biology, 4, 688. doi:10.1038/s42003-021-02193-z. https://pubmed.ncbi.nlm.nih.gov/34099862/

3. Liu, Xicheng, Wei, Wendi, Li, Xiaowei, Zhao, Liping, Xi, Rongwen. 2017. BMI1 and MEL18 Promote Colitis-Associated Cancer in Mice via REG3B and STAT3. In Gastroenterology, 153, 1607-1620. doi:10.1053/j.gastro.2017.07.044. https://pubmed.ncbi.nlm.nih.gov/28780076/

4. van Ampting, Marleen T J, Loonen, Linda M P, Schonewille, Arjan J, Wells, Jerry M, Bovee-Oudenhoven, Ingeborg M J. 2012. Intestinally secreted C-type lectin Reg3b attenuates salmonellosis but not listeriosis in mice. In Infection and immunity, 80, 1115-20. doi:10.1128/IAI.06165-11. https://pubmed.ncbi.nlm.nih.gov/22252863/

5. Bluemel, Sena, Wang, Lirui, Martino, Cameron, Zengler, Karsten, Schnabl, Bernd. 2018. The Role of Intestinal C-type Regenerating Islet Derived-3 Lectins for Nonalcoholic Steatohepatitis. In Hepatology communications, 2, 393-406. doi:10.1002/hep4.1165. https://pubmed.ncbi.nlm.nih.gov/29619418/

6. Shindo, Ryodai, Katagiri, Takaharu, Komazawa-Sakon, Sachiko, Kameda, Hideto, Nakano, Hiroyasu. 2020. Regenerating islet-derived protein (Reg)3β plays a crucial role in attenuation of ileitis and colitis in mice. In Biochemistry and biophysics reports, 21, 100738. doi:10.1016/j.bbrep.2020.100738. https://pubmed.ncbi.nlm.nih.gov/32072024/