Mark S. Sundrud, Ph.D.
The Sundrud lab develops and applies genetic, chemical and biochemical tools to identify and target mechanisms underlying T cell-driven inflammatory diseases. Autoimmune or chronic inflammatory disorders, such as type 1 diabetes (T1D), multiple sclerosis, psoriasis and inflammatory bowel disease (IBD), are debilitating diseases that affect nearly 1 in 10 American adults and require expensive life-long therapy. CD4+ T helper (TH) cells, which become programmed to secrete polarized sets of either pro- or anti-inflammatory cytokines and instruct other immune or parenchymal cells how to clear infections, are essential for both protective and pathogenic immune responses. Thus, our lab focuses on both fundamental and translational mechanisms by which functional fates of TH cells are established during healthy immune responses, and how/when/where these TH cell fates and functions become perturbed during autoimmune or chronic inflammatory disease pathogenesis.
We have contributed important insights into the development and function of both IL-17-secreting (Th17) cells – a uniquely pro-inflammatory TH cell subset that operates primarily at barrier surfaces – as well as tissue-protective regulatory subsets, including Foxp3+ T regulatory (Treg) cells and Foxp3- type 1 regulatory (Tr1) cells. More recent work from the lab has elucidated novel pathways by which these and other TH cell subsets maintain tolerance and immune homeostasis upon infiltration of the small intestinal mucosa. A working hypothesis is that these pathways, which involve local upregulation of xenobiotic-sensing nuclear receptors (CAR/Nr1i3) and transporters (MDR1/Abcb1a, Abcb1b), are deployed to prevent toxicity and inflammation in the presence of a discrete and fundamental class of intestinal metabolites, called bile acids, which circulate postprandially between the liver and small intestine.
The gut is a major immunological organ where host-microbe interactions shape both local and systemic immune tolerance. However, current views of intestinal immune regulation ignore fundamental differences in the function and metabolite composition of the two distinct organs that comprise the gut—the small and large intestine (or SI and LI). This impedes a more detailed understanding of immune regulatory mechanisms along the intestinal tract, and limits efforts to develop safer, more targeted treatments for the two major forms of human inflammatory bowel diseases (IBDs), ulcerative colitis and small bowel Crohn's disease. We hypothesize that mucosal CD4 T cells use different sets of ligand-regulated nuclear receptors (NRs) in the SI and LI to control key regulatory functions, including IL-10 expression, to local concentration gradients of bile- and microbe-derived metabolites. On one hand, we have discovered that Foxp3– effector (Teff) subsets in the SI—including Th1 and Th17 cells—utilize the nuclear xenobiotic receptor, constitutive androstane receptor (CAR/Nr1i3), to direct a 'hepatocyte-like' transcriptional response to contend with high local bile acid (BA) concentrations, which are far greater in SI than in LI (millimolar vs micromolar) due to 'enterohepatic' circulation—where primary BAs synthesized in the liver, stored in the gallbladder, and secreted into the duodenum are actively reabsorbed by specialized enterocytes in the ileum for portal recirculation to the liver. Because BAs are lipophilic, they can be toxic and pro-inflammatory, and several nuclear receptors—including CAR—have evolved to suppress BA toxicity. These studies suggest that enterohepatic circulation establishes a unique SI microenvironment that is distinct from that in the LI and requires unique transcriptional machinery to protect T cells in the SI. Conversely, the LI harbors 103-107 times more bacteria than SI, and ~1000-fold lower BA concentrations. Accordingly, microbes and their metabolites—short chain fatty acids (SCFAs; e.g., butyrate), secondary BAs (produced via microbial metabolism of residual primary BAs)—are central to immune regulation in the LI. SCFAs inhibit histone deacetylase enzymes (HDACs) and stabilize Foxp3 gene expression in peripherally-induced T regulatory cells (iTregs), whereas secondary BAs appear to promote regulatory functions of RORt+ Tregs in the LI through another NR, vitamin D receptor (VDR). Thus, while antigens from the enteric flora prime both pro- and anti-inflammatory T cell responses throughout the gut, marked concentration gradients of bile- and bacteria-derived metabolites in the SI vs. LI are sensed by different NRs to execute compartmentalized T cell regulatory functions. In testing this hypothesis, we will apply cutting-edge genomics and computational approaches to comprehensively map the contributions of each of the 49 mouse NRs to specialized regulatory functions in the SI and LI in vivo, using IL-10 expression as the primary screening target. We will also interrogate the regulation and molecular functions of two key NRs, CAR/Nr1i3 and VDR/Nr1i1, in SI type 1 regulatory (Tr1) and LI iTreg cells, respectively. These studies will advance understanding of lymphocyte specialization in the gut, and inform new approaches to treat IBDs.
Current Grant Support
|5R01AI143821||Sundrud||02/01/2019 – 01/31/2024|
|Title: Determinants of bile acid-dependent T cell regulation in the intestine
The goal of this program is to define how the constitutive androstane receptor (CAR) and its downstream transcriptional targets interact with bile acids to enforce small bowel immune homeostasis.
Title: Nuclear Receptor Networks in Mucosal Immune Regulation
This program will unmask non-redundant nuclear receptor (NR) pathways that mucosal T cells use in the small and large intestines to sense and respond to opposing host and microbial metabolite gradients.
|1R21AI154039-01A1||Sundrud||09/01/2021 – 08/31/2023|
Title: Transcript-selective translational control of Th17 cell development and function
This project seeks to elucidate mechanisms by which mammalian prolyl-tRNA synthetase (EPRS) executes transcript-selective translational silencing of transcription factors necessary for Th17 cell development and function.
|1 R01 AI164772-01||Sundrud||9/23/2021 – 8/31/2026|
Title: Nuclear receptor control of T cell function in discrete intestinal microenvironments
The project examines the non-redundant functions two nuclear receptors (CAR/Nr1i3, VDR, Nr1i1) in small and large intestinal immune homeostasis, respectively.
Mark S. Sundrud, Ph.D.
MT Abreu, JM Davies, MA Quintero, A Delmas, S Diaz, CD Martinez, T Venables, A Reich, G Crynen, A Deshpande, DH Kerman, OM Damas, I Fernandez, AM Santander, J Pignac-Kobinger, JF Burgueno, MS Sundrud. 2021. Transcriptional behavior of regulatory T cells predicts IBD patient responses to vedolizumab therapy. IBD Journal – in press.
ML Chen, X Huang, H Wang, Y Liu, J Shang, A Eliason, C Hegner, H Park, B Frey, G Wang, DJ Kojetin, CT Weaver, ME Pipkin, DD Moore, MS Sundrud. 2021. CAR directs T cell adaptation to bile acids in the small intestine. Nature. May;593(7857):147-151. doi: 10.1038/s41586-021-03421-6. Epub 2021 Apr 7.
R Wang, S Campbell, M Amir, MA Bassette, A Eliason, MS Sundrud, TM Kamenecka, LA Solt. 2021. Genetic and pharmacological inhibition of the nuclear receptor RORa regulates TH17 driven inflammatory disorders. Nat Comm. Jan 4;12(1):76.
AR Basson, C Chen, F Sagl, A Trotter, I Bederman, A Gomez-Nguyen, MS Sundrud, S Ilic, F Cominelli, A Rodriguez-Palacios. Regulation of Intestinal Inflammation by Dietary Fats. Front Immunol. 2021 Feb 2;11:604989. doi: 10.3389/fimmu.2020.604989. eCollection 2020.
ML Chen, A Sun, W Cao, A Eliason, KM Mendez, AJ Getzler, S Tsuda, H Diao, C Mukori, NE Bruno, SY Kim, ME Pipkin, SB Koralov, MS Sundrud. 2020. Physiologic expression and function of the multidrug transporter MDR1 in cytotoxic T lymphocytes. J Exp Med. May 4;217(5):e20191388.
Y Kim, MS Sundrud, C Zhou, M Edenius, D Zocco, K Powers, EH Noss, MB Brenner, A Rao, R Mazitschek, CY Yeo, M Whitman, TL Keller. 2020. Aminoacyl-tRNA Synthetase Inhibition Activates a Novel Pathway that Branches from the Canonical Amino Acid Response in Mammalian Cells. Proc Natl Acad Sci USA. Apr 21;117(16):8900-8911. #co-first author.
A Basson , A LaSalla , G Lam , D Kulpins , E Moen , MS Sundrud , J Miyoshi , S Ilic , B Theriault , F Cominelli, A. Rodriguez-Palacios. 2020. Understanding 'artificial' mouse-microbiome heterogeneity and six actionable themes to increase study power and reproducibility. Sci Rep. Mar 19;10(1):5039.