Inflammatory bowel disease (IBD) is the collective term for chronic idiopathic inflammatory diseases of the intestine, most notably Crohn's Disease (CD) and Ulcerative Colitis (UC), which together affect 1.4 million people in the US and 2.2 million people in Europe. IBD is associated with elevated levels of a number of acute phase proteins (APP) that drive or dampen the inflammatory response. Exploration of the biologic activities of APP has resulted in the development of targeted biological therapeutic agents. Indeed, agents that directly antagonize pro-inflammatory mediators or mimic anti-inflammatory molecules are currently being used and/or developed to treat IBD. However, the biologic activity, and thus therapeutic potential, of some of the most dynamically regulated APP remain unexplored. For example, while levels of the APP lipocalin-2 (Lcn2) increase by several log orders of magnitude in various inflammatory conditions, including murine colitis and human IBD, the extent to which Lcn2 drives or dampens gut inflammation remains unexplored. In addition to its elevated expression being associated with colitis, the multifaceted biologic activity of Lcn2 (as well as that of its human ortholog, Neutrophil Gelatinase-Associated Lipocalin) or NGAL suggests it may play a central role in IBD. Specifically, Lcn2 exerts potent antibacterial activity mediated by sequestering bacterial siderophores and thereby preventing bacteria from scavenging iron from lower affinity host proteins. In addition, Lcn2 participates in iron transport stabilizing highly reactive catalytic iron by chelation. Accordingly, it has been shown that Lcn2 deficient mice are highly susceptible to bacterial and LPS-induced sepsis. We hypothesize that Lcn2's control over iron homeostasis is not limited to the extreme events such as sepsis but, rather, that the dynamic regulation of Lcn2 from low-grade inflammation to acute and chronic colitis plays an important role in preserving gut neutrophil function as well as iron/microbiota homeostasis. Consequently, the goal of this proposal is to investigate the role and mechanism of action of Lcn2 in intestinal inflammation. Establishing the role of this dynamically regulated protein will advance our knowledge of pathogenesis and perhaps allow development of novel therapeutic strategies to treat human IBD. We anticipate that these studies will demonstrate a key role for Lcn2 in protecting the gut. Given its small size, simple structure and biologic activiy in the absence of post-translational modification, Lcn2 may be exploitable as a treatment for intestinal inflammation.
Lipocalin 2 (Lcn2) is an innate immune protein that is highly unregulated during inflammatory conditions, including inflammatory bowel disease. Lcn2 and its human ortholog neutrophil gelatinase---associayed lipocalin (NGAL), can bind and stabilize catalytic iron, transport iron and aid in the sequestering bacterial siderophores andinhibit their iron acquisition from host proteins. It is also required for neutrophilmigration, adhesion and function. We hypothesize that Lcn2/NGAL plays a key role in neutrophil/iron/microbiota homeostasis during intestinal inflammation and may influence the pathogenesis of human IBD. We will test our hypothesis in acute and chronic murine colitis using Lcn2 knock out, transgenic and bone marrow chimeras. Further, we will study the intestinal microbiota alterations mediated by Lcn2 and also intervening with dietary iron.
|Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit et al. (2018) Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Cell 175:679-694.e22|
|Xiao, Xia; Saha, Piu; Yeoh, Beng San et al. (2018) Myeloperoxidase deficiency attenuates systemic and dietary iron-induced adverse effects. J Nutr Biochem 62:28-34|
|Saha, Piu; Chassaing, Benoit; Yeoh, Beng San et al. (2017) Ectopic Expression of Innate Immune Protein, Lipocalin-2, in Lactococcus lactis Protects Against Gut and Environmental Stressors. Inflamm Bowel Dis 23:1120-1132|
|Xiao, Xia; Yeoh, Beng San; Saha, Piu et al. (2017) Modulation of urinary siderophores by the diet, gut microbiota and inflammation in mice. J Nutr Biochem 41:25-33|
|Singh, Vishal; Yeoh, Beng San; Nilsen-Hamilton, Marit et al. (2017) Data on IL-10R neutralization-induced chronic colitis in Lipocalin 2 deficient mice on BALB/c background. Data Brief 11:588-592|
|Saha, Piu; Yeoh, Beng San; Olvera, Rodrigo A et al. (2017) Bacterial Siderophores Hijack Neutrophil Functions. J Immunol 198:4293-4303|
|Xiao, Xia; Yeoh, Beng San; Vijay-Kumar, Matam (2017) Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation. Annu Rev Nutr 37:103-130|
|Yeoh, Beng San; Aguilera Olvera, Rodrigo; Singh, Vishal et al. (2016) Epigallocatechin-3-Gallate Inhibition of Myeloperoxidase and Its Counter-Regulation by Dietary Iron and Lipocalin 2 in Murine Model of Gut Inflammation. Am J Pathol 186:912-26|
|Etienne-Mesmin, Lucie; Vijay-Kumar, Matam; Gewirtz, Andrew T et al. (2016) Hepatocyte Toll-Like Receptor 5 Promotes Bacterial Clearance and Protects Mice Against High-Fat Diet-Induced Liver Disease. Cell Mol Gastroenterol Hepatol 2:584-604|
|Saha, Piu; Singh, Vishal; Xiao, Xia et al. (2016) Data on importance of hematopoietic cell derived Lipocalin 2 against gut inflammation. Data Brief 8:812-6|
Showing the most recent 10 out of 22 publications