Gwendalyn J. Randolph, PhD
Emil R. Unanue Professor, Pathology & Immunology
- Phone: 314-286-2345
- Email: email@example.com
- Professor, Medicine
- Website under reconstruction
- Bachelor of Sciences in Biology: Temple University, Philadelphia, PA (1991)
- PhD, Molecular and Cellular Pathology: State University of New York at Stony Brook, Stony Brook, NY (1995)
- Postdoctoral Fellow: Rockefeller University, New York, NY (1997)
- Postdoctoral Fellow/Instructor: Weill Cornell Medical School, New York, NY (2000)
- Aaron Janoff Award for Experimental Pathology, SUNY Stony Brook, 1995
- Faculty Council Award, Mount Sinai School of Medicine, 2003
- Dr. Harold and Golden Lamport Research Award, Mount Sinai, 2005
- Established Investigator Award, American Heart Association, 2007
- Pioneer Award, National Institutes of Health, 2015
- NIH MERIT Award, 2016 (associated with grant AI049453 held continuously since July 2000)
- The Special Recognition Award in Atherosclerosis, American Heart Association, 11/2019
- Clarivate Highly Cited Researcher, 2017-2021
- NIDDK Catalyst Award, 2021
My entire career has been focused on defining the trafficking of cellular and molecular cargo out of tissues to distal lymph nodes or downstream organs and the relationship of such trafficking to chronic inflammatory disease. Early on, I focused on monocytes, aiming to define whether the ability of an inflamed tissue to clear monocyte-derived cells that had accumulated during inflammation might involve, at least in part, their migratory egress from the tissue via a return to blood or lymph. I devised approaches to label monocytes with phagocytic cargo to address this question and found trafficking of some of the labeled cells to lymph nodes, with the monocyte-derived cells that emigrated to lymph nodes possessing some features of dendritic cells. This work led my group to develop strategies to study and characterize both conventional dendritic cell migration and monocyte-derived cell migration through lymphatics to lymph nodes in tissues like skin, lung, and bladder. We also considered the lymphatic vasculature and defined how the lymphatic remodeling was coordinated in lymph nodes, via lymphotoxin-expressing B cells, to promote dendritic cell entry from lymph in balance with the recruitment of lymphocytes coming in from the HEV. From the monocyte perspective, we compared and characterized the phenotype and migratory properties of human and mouse monocyte subsets, with an interest in understanding what features led a monocyte to become an emigratory cell versus a macrophage that does not readily emigrate to lymph nodes from tissues.
While this basic science was ongoing, I developed a strong interest in atherosclerosis, a disease scenario of significant clinical relevance where monocytes were central participants and where little work to study the dynamics behind their accumulation in plaques was being done (but where assumptions existed). The technical challenge of studying cell migration in a location like atherosclerotic plaque, near the beating heart inside the chest cavity, was high. Nonetheless, as one of the earliest groups to bring the sophisticated tools of immunology to atherosclerotic plaque research, we devised novel labeling and lineage tracing strategies that quantitatively defined the relative importance of monocyte recruitment, migratory egress, death and proliferation in atherosclerosis. We extended these findings to reveal, through single cell sequencing, that recently recruited monocytes, not the notorious lipid laden foam cell, was the source of most proinflammatory cytokines that sustain plaque progression, and we recently identified a PET tracer approach that may have translational utility in identifying those plaques most actively recruiting monocytes.
As this work was ongoing, we began to transcriptionally profile macrophages resident in a variety of organs as part of the Immunological Genome Project. This work led to identification of a core set of genes that defined macrophages, while revealing striking tissue-specific profiles for resident macrophages if different organs. We were drawn to the peritoneal cavity as a site to focus some of this work, as we had long tracked monocytes through a range of acute inflammatory responses in the peritoneal cavity as a general comparison for how monocytes behaved in sites like atherosclerotic plaque. We first predicted and later, simultaneously with other groups, proved that the transcription factor Gata6 governs the identity and life cycle of the resident peritoneal macrophage. This has led to a series of studies, many ongoing, that will define the complexity of specialization of several different types of resident macrophages in the body cavity, and we are now characterizing their human counterparts.
Although our work in acute and chronic inflammation studies cited above revealed that not many monocyte-derived cells emigrate into lymph once their predominant differentiation to macrophages begins upon arrival to sites of inflammation, we did not abandon our interest in lymphatic transport. Indeed, our interest only grew stronger. As part of the atherosclerosis community, I took an interest in lipoproteins and realized that several lipoproteins also make long-distance trips through from tissue to tissue through lymphatic or blood vessels. When we started this research about a decade ago, it was vaguely understood that lipoproteins like HDL would traffic in and out of tissues as part of their lifecycle, but little was known about the details of such trafficking. We demonstrated that high-density lipoprotein (HDL), which is known for returning cholesterol to the liver from various tissues, depended upon lymphatic vessels to leave most tissue sites, including the artery wall. We developed a photoconvertible tagged apoA1 knock-in mouse that allowed us to shine light on any organ of the mouse and track the migratory fate of HDL that originated from that tissue. This may be one of the few uses of molecular photoactivation to track organ to organ trafficking in the literature. With this tool, we further demonstrated how the immune response in diseases like psoriasis can promote the undesirable onset of cardiovascular comorbidities. Specifically, Th17 responses creates a tissue microenvironment poorly conducive to the passage of HDL particles through the interstitium and one that supports arterial stiffness that contributes to hypertension. This may have evolved to promote trapping of organisms to aid in immunity, but it also traps lipoproteins, including HDL.
As we turned to considering the trafficking of HDL and other lipoproteins out of tissues, we were drawn to new research questions in the intestine. In Crohn’s disease, we set out to explore the long-discussed but not yet demonstrated concept that disease pathogenesis is linked to impaired lymphatic transport. Through 3-D imaging of patient resection tissue, we found evidence that the lymphatic outflow from the ileum of Crohn’s disease patient might not reach draining lymph nodes because de novo tertiary lymphoid follicles appeared to impinge upon the major lymphatic trunks that routed into lymph nodes. In a mouse model of ileitis, we have illustrated, using photoconversion and intravital imaging tools, that indeed tertiary lymphoid follicles in the mesentery strongly block cellular and molecular passage through the lymphatics, while setting up the lymphoid follicles as sites of leak and lymph back flow. We were struck by data from the Pediatric Risk Cohort revealing that the main protein in HDL, apoA1, is among the top downregulated genes in patients with deep ulcering ileal disease. We set out to ask why the gut even bothers to make HDL, when the liver is known to make most of the HDL in systemic blood. We discovered that, at least in mice and supported by data we obtained in humans, HDL is principally made by intestinal epithelium of the ileum in a form called HDL3 that is specialized for the neutralization of microbial lipids like LPS. We found that if the ileum does not produce HDL but receives an insult (from high fat diet, alcohol, or surgical resection), it leaks more LPS to the liver and this in turn drives inflammation and ultimately liver fibrosis. Our photoactivatable HDL knock-in mouse allowed us to show that the intestine specifically routes the HDL to the portal vein, not the lymphatics, as it does in other tissues, putting it in the exact location that would allow it to best protect the liver from injury. In preclinical mouse models, if we deliver drugs delivered orally to raise the level of intestine-secreted HDL, we protect the liver from fibrosis in a manner dependent upon intestinal HDL biogenesis. We are hopeful that these recent findings have the potential to translate into treatments to combat liver inflammatory disease or fibrosis and drive a way of renewed research on HDL that focuses on its role in limiting the proinflammatory signalling of microbial products that disseminate from the intestine.
I enjoy training future scientists and have hosted the training of more than 2 dozen postdocs, more than 90% of whom have gone on to start their own research laboratories in the USA and countries around the world.
- Immunology Program Director
- Biomedical Engineering
|N Zhang, SH Kim, A Gainullina, EC Erlich, EJ Onufer, J Kim, RS Czepielewski, BA Helmink, JR Dominguez, BT Saunders, J Ding, JW Williams, JX Jiang, BH Segal, BH Zinselmeyer, *GJ Randolph, *KW Kim. 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|
|Rafael S. Czepielewski, Emma C. Erlich, Emily J. Onufer, Shannon Young, Brian T. Saunders, Yong-Hyun Han, Mary Wohltmann, Peter L. Wang, Ki-Wook Kim, Shashi Kumar, Chyi-Song Hsieh, Joshua P. Scallan, Ying Yang, Bernd H. Zinselmeyer, Michael J. Davis, Gwendalyn J. Randolph. 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|
|YH Han, EJ Onufer, RW Sprung, WS Davidson, RS Czepielewski, M Wohltmann, MG Sorci-Thomas, BW Warner, GJ Randolph. 2021. Enterically derived high-density lipoprotein restrains liver injury through the portal vein, Science, 373, 410; DOI: 10.1126/science.abe6729|
|O Baba, A Elvington, D Sultan, GS Heo, X Zhang, H Luehmann, L Detering, M Szpakowska, A Chevigne, Y Liu, GJ Randolph. 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.|
|LH Huang, P Deepak, MA Ciorba, B Mittendorfer, BW Patterson, GJ Randolph. 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|
|JW Williams, K Zaitsev, KW Kim S Ivanov, BT Saunders, PR Schrank, K Kim, A Elvington, SH Kim, C Tucker, M Wohltmann, BT Fife, S Epelman, M Artyomov, KJ Lavine, BH Zinselmeyer, JH Choi, GJ. Randolph. 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|
|PL Wang, AKY Yim, K Kim, D Avey, RS Czepielewski, M Colonna, *J Milbrandt, *GJ Randolph. 2020. Peripheral nerve resident macrophages share tissue-specific programming and features of activated microglia. Nature Communications, 11(1):2552. doi: 10.1038/s41467-020-16355-w|
|Zhang N, Czepielewski RS, Jarjour NN, Erlich EC, Esaulova E, Saunders BT, Grover SP, Cleuren AC, Broze GJ, Edelson BT, Mackman N, Zinselmeyer BH, Randolph GJ. (2019). Expression of factor V by resident peritoneal macrophages boosts host defense in the peritoneal cavity. J. Exp. Med, 216: 1291-6. PMCID 6547866|
|Angeli V, Ginhoux F, Llodrá J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, and Randolph GJ. B cell driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 2006;24(2):203-215 PMID: 16473832|
Lab Phone: 314-286-2361
Office Location: CSRB-NT, 10th Floor, Room 1020