Gwendalyn J. Randolph, PhD
By focusing on the trafficking of molecules and cells out of tissues, my research laboratory integrates immunology and vascular biology with the study of disease mechanisms linked to inflammation. In parallel to the study of disease mechanisms, we carry out basic science essential to the interpretation of observations in the disease context. Early in my career, I worked on the fate of monocytes as they differentiated to macrophages or dendritic cells, with a particular interest in the development of their ability to traffic out of inflammatory tissues via lymphatic vessels to lymph nodes, as we considered the role of such trafficking in the ability of an inflammatory state to resolve. Over time, in interacting with scientists bringing diverse expertise to atherosclerosis, where I worked on monocyte trafficking for a number of years, my laboratory developed an interest in the trafficking of not just cells but also of molecules, particularly lipoproteins out of tissues, since the inability of lipoproteins to reach key sites or to become trapped can affect the course of inflammation. We developed approaches to examine trafficking of lipoproteins through tissue interstitial spaces, asking (as we had done for immune cells) how reliant on functional lymphatics was a lipoprotein's ability to leave tissues appropriately in order to promote key processes like reverse cholesterol transport. In recent years, we realized that the tri-partite expertise we developed (immune cell trafficking, lipoprotein trafficking, lymphatic vessel biology) could be put to work on new questions in disease states less well understood than atherosclerosis. One such question is whether lymphatics that carry lipid nutrients, immune cells, and other cargo away from the gut become dysfunctional in inflammatory diseases like Crohn's disease. We are thus actively transitioning our research to understanding the trafficking of cellular and molecular cargo out of the intestine and associated mesentery.
A major concern of the intestinal mucosa is to execute its role in absorption of nutrients while minimizing inflammatory or adverse immune interactions with the microbiome. Managing absorption entails not only sorting of nutrients by intestinal epithelial cells but also delivery of those nutrients to specialized blood and lymphatic vessels present in each villus of the small intestine. In turn, the blood and lymphatic vessels that collectively manage outflow from the gut may need to rely on specialized mechanisms that operate to limit dissemination of microbial signals to distal sites like the lung or the liver to avoid downstream organ injury. It is now appreciated, for instance, that alcoholic and nonalcoholic liver damage is driven substantially by microbial transit from the gut to the liver via the portal vein. Likewise, pulmonary damage can ensue in response to injurious cargo in lymph that gains access to blood via the thoracic duct and quickly next flows to the lungs. Yet mechanisms protecting against dissemination of microbial signals from the intestinal mucosa remain incompletely understood, possibly making planned manipulations of the mucosal barrier, as in vaccination or disease therapy, riskier than needed or resulting in surprises. For instance, our preliminary data suggest that the documented and seemingly counterintuitive liver damage that can result from anti-TNF neutralizing antibody therapy to treat inflammatory disease of the bowel may be due, at least in part, to disruption of leukocyte-mediated surveillance of the draining venous vasculature that removes microbes that escape the intestinal mucosal before they arrive to the liver. To fill in these basic knowledge gaps, we propose herein to delineate how different regions of the intestine program leukocyte-dependent and leukocyte-independent strategies to protect downstream cells and tissues against dissemination of microbial signals. In aim 1, we focus on mechanisms operative in phagocytic removal from gut-draining venous blood of whole microbes that escape the intestinal mucosal barrier and otherwise deliver the microbes to deeper tissues or distal locations. In aim 2, we will compare how the small bowel and colon may differentially transport and neutralize soluble microbial signals, like LPS, that can inadvertently escape the epithelial barrier to promote inflammation. This effort will include comprehensive proteomic and lipidomic evaluation of lymph and blood draining different regions of the gut mucosa, working with expert collaborators and taking advantage of our laboratory's expertise in lymphatic biology and recent studies in the transport of intestinal cargo into gut-draining venous blood.
Current Grant Support
|R01 DK119147||Multi PI: Randolph and Brad Warner||12/1/18-11/30/23|
|Lymphatic remodeling and transport of dietary fats in short gut syndrome|
|R37 AI049653||PD/PI : Randolph, GJ||12/01/21-11/30/26|
Differentiation and Function of Monocytes and Macrophages
|Rainin Foundation Synergy Award||Triple PI: Randolph GJ, Davis MJ, Kohan A||03/01/2020-2/28/23|
|Human and experimental animal studies to identify mechanisms governing lymph transport in Crohn's disease|
|T32 AI 007163 041||PD/PI: Randolph, GJ||1978-2024; current cycle 2019-2024|
|U01 AI 163064||PD/PI: Randolph, GJ||07/01/2021-06/30/2026|
|Gut region-specific mechanisms that limit dissemination of microbials signals from the intestine|
|Defining the lymphatic basis of protein-losing enteropathy after Fontan palliation or inflammatory gut disease|
|R01I68044||PD/PI||04/01/22 – 3/31/2027|
|Mechanisms that alter lymphatic transport in inflammatory bowel disease|
|P01 AG078106||PD/PI: Kipnis, J; Randolph project leader||08/01/22 – 5/31/2027|
|Project 3: Interplay between meningeal lymphatics, high-density lipoproteins, and border macrophages in cerebral amyloid angiopathy|
|P01 AGI68044||PD/PI: Kipnis J; Randolph, core leader||08/01/22 – 5/31/2027|
|Imaging and surgical core|
Gwendalyn J. Randolph, PhD.
Uzzan M, Martin JC, Mesin L, Livanos AE, Castro-Dopico T, Huang R, Petralia F, Magri G, Kumar S, Zhao Q, Rosenstein AK, Tokuyama M, Sharma K, Ungaro R, Kosoy R, Jha D, Fischer J, Singh H, Keir ME, Ramamoorthi N, Gorman WEO, Cohen BL, Rahman A, Cossarini F, Seki A, Leyre L, Vaquero ST, Gurunathan S, Grasset EK, Losic B, Dubinsky M, Greenstein AJ, Gottlieb Z, Legnani P, George J, Irizar H, Stojmirovic A, Brodmerkel C, Kasarkis A, Sands BE, Furtado G, Lira SA, Tuong ZK, Ko HM, Cerutti A, Elson CO, Clatworthy MR, Merad M, Suárez-Fariñas M, Argmann C, Hackney JA, Victora GD, Randolph GJ, Kenigsberg E, Colombel JF, Mehandru S. Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat Med. 2022 Apr;28(4):766-779. doi: 10.1038/s41591-022-01680-y.
Czepielewski RS., Erlich EC., Onufer EJ., Young S, Saunders BT, Han YH, Wohltmann M, Wang PL, Kim KW, Kumar S, Hsieh CS, Scallan JP, Yang Y, Zinselmeyer BH, Davis MJ, Randolph GJ. 2021. Ileitis-associated mesenteric tertiary lymphoid organs arise at lymphatic valves and impede lymph flow in response to tumor necrosis factor. Immunity, 54(12):2795-2811. doi: 10.1016/j.immuni.2021.10.003. PMCID: 8678349
Zhang N, Kim SH, Gainullina A, Erlich EC, Onufer EJ, Kim J, Czepielewski RS, Helmink BA, Dominguez JR, Saunders BT, Ding J, Williams JW, Jiang JX, Segal BH, Zinselmeyer BH, Randolph GJ, Kim KW. 2021. LYVE1hi macrophages reside in mesothelium and promote omentum-independent ovarian tumor growth in the peritoneum. J. Exp. Med., 218(12):e20210924. doi: 10.1084/jem.20210924. *joint senior author; ^primary corresponding author. PMCID: 8575007
Han YH, Onufer EJ, Sprung RW, Davidson WS, Czepielewski RS, Wohltmann M, Sorci-Thomas MG, Warner BW, Randolph GJ. 2021. Enterically derived high-density lipoprotein restrains liver injury through the portal vein. Science, 373, 410; DOI: 10.1126/science.abe6729. [Feature articles in Immunity, and Nature Rev Gastro Hepatol]
Baba O, Elvington A, Sultan D, Heo GS, Zhang X, Luehmann H, Detering L, Szpakowska M, Chevigne A, Liu Y, Randolph GJ. 2021. CXCR4 on atherosclerotic plaque endothelium predicts the magnitude of monocyte recruitment and is readily targeted by PET tracers. Arterio Thromb Vasc Biol 41(2):822-836. doi: 10.1161/ATVBAHA.120.315053. [editorial comment, same issue]
Huang LH, Deepak P, Ciorba MA, Mittendorfer B, Patterson BW, Randolph GJ. 2020. Postprandial chylomicron output and transport through intestinal lymphatics are not impaired in active Crohn's disease. Gastroenterology, 159:1955-9156. doi: 10.1053/j.gastro.2020.07.012. [letter to the editor published, along with our reply, April 2021]
Williams JW, Zaitsev K, Kim KW, Ivanov S, Saunders BT, Schrank PR, Kim K, Elvington A, Kim SH, Tucker C, Wohltmann M, Fife BT, Epelman S, Artyomov M, Lavine KJ, Zinselmeyer BH, Choi JH, Randolph GJ. Limited proliferation capacity of aorta intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression. Nature Immunology, 21:1194-1204. doi. 10.1038/s41590-020-0768-4