Immunology Faculty Member - Timothy Hla

Timothy Hla

Boston Children's Hospital
Dept of Surgery, Karp Building, 12.211
1 Blackfan Circle
Boston, MA 02115
Tel: (617) 919-2179
Email: Timothy.Hla@childrens.harvard.edu



Lipid signaling in immunity and inflammatory disease

My laboratory studies the biology of the bioactive lipid mediator- sphingosine 1-phosphate (S1P), a fundamental regulator of immune and vascular systems. The vertebrate immune system co-evolved with the closed circulatory system in such a way that complex trafficking paradigms are employed for the hematopoietic cells to enter and exit the vascular and lymphatic conduits in various organs. S1P, an extracellular ligand that activates cell-surface G protein-coupled receptors, is present in high concentration in the circulatory system and provides an essential egress cue for T and B lymphocyte trafficking and retention in various organs. S1P receptor-based small molecules are already in the clinic for the treatment of multiple sclerosis and are being tested in clinical trials for a number of autoimmune diseases including ulcerative colitis and psoriasis.

We are seeking to increase our understanding of how S1P is produced, released, transported in vivo, signals via its cell-surface receptors and achieves specific biological outcomes in vascular, immune and nervous systems. We are also involved in projects that develop novel therapeutics based on S1P signaling.

We have recently developed mouse models for the gain- and loss-of-function of S1P receptors. Using these mouse models, we are exploring the role of S1P receptors in myeloid cells. We are trying to understand the role of myeloid S1P receptors-1, 2 and 3 in immune/ vascular interactions, T and B cell development and regulation of the immune response. These studies are anticipated to increase our understanding of how S1P regulates normal immunity and homeostasis, but also to appreciate how this signaling system impacts on inflammatory diseases, cancer and vascular pathologies.

S1P signaling is greatly influenced by its chaperones, such as HDL-bound ApoM, which direct specific biological responses. We are defining the molecular mechanisms involved in chaperone-based S1P signaling and developing a bio-therapeutic based on S1P chaperone ApoM to control vascular and inflammatory diseases.

S1P production in the immune-privileged organs such as the brain is compartmentalized from that of the peripheral organ systems. Yet, S1P is an essential mediator in the central nervous system (CNS) and plays critical roles in neurotransmission, blood brain barrier and neuroinflammation. We are trying to understand the cellular and molecular mechanisms involved in S1P transport, signaling and biology in neuroinflammatory and neurovascular diseases. We believe that this effort will help in the development of novel therapeutics in the treatment of CNS diseases such as multiple sclerosis, stroke and dementias.




Last Update: 5/10/2017



Publications

For a complete listing of publications click here.

 


 

1: Yanagida K, Hla T. Vascular and Immunobiology of the Circulatory Sphingosine
1-Phosphate Gradient. Annu Rev Physiol. 2017 Feb 10;79:67-91. doi:
10.1146/annurev-physiol-021014-071635. Epub 2016 Oct 21. PubMed PMID: 27813829.

2: Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, Dahlbäck B,
Kono M, Proia RL, Smith JD, Hla T. HDL-bound sphingosine 1-phosphate acts as a
biased agonist for the endothelial cell receptor S1P1 to limit vascular
inflammation. Sci Signal. 2015 Aug 11;8(389):ra79. doi:
10.1126/scisignal.aaa2581. Erratum in: Sci Signal. 2015 Oct 27;8(400):er8.
Obinata, Hideru [added]. PubMed PMID: 26268607; PubMed Central PMCID: PMC4768813.

3: Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL, Kono M, Proia RL,
Steinman L, Han MH, Hla T. HDL-bound sphingosine-1-phosphate restrains
lymphopoiesis and neuroinflammation. Nature. 2015 Jul 16;523(7560):342-6. doi:
10.1038/nature14462. Epub 2015 Jun 8. PubMed PMID: 26053123; PubMed Central
PMCID: PMC4506268.

4: Lu YC, Chang SH, Hafner M, Li X, Tuschl T, Elemento O, Hla T. ELAVL1 modulates
transcriptome-wide miRNA binding in murine macrophages. Cell Rep. 2014 Dec
24;9(6):2330-43. doi: 10.1016/j.celrep.2014.11.030. Epub 2014 Dec 18. PubMed
PMID: 25533351; PubMed Central PMCID: PMC4277505.

5: Garris CS, Wu L, Acharya S, Arac A, Blaho VA, Huang Y, Moon BS, Axtell RC, Ho
PP, Steinberg GK, Lewis DB, Sobel RA, Han DK, Steinman L, Snyder MP, Hla T, Han
MH. Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation
exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol. 2013
Nov;14(11):1166-72. doi: 10.1038/ni.2730. Epub 2013 Sep 29. PubMed PMID:
24076635; PubMed Central PMCID: PMC4014310.

6: Thangada S, Khanna KM, Blaho VA, Oo ML, Im DS, Guo C, Lefrancois L, Hla T.
Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes
determines lymphocyte egress kinetics. J Exp Med. 2010 Jul 5;207(7):1475-83. doi:
10.1084/jem.20091343. Epub 2010 Jun 28. PubMed PMID: 20584883; PubMed Central
PMCID: PMC2901064.



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