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: 1/20/2020



Publications

For a complete listing of publications click here.

 


 

1: Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and
therapy. Science. 2019 Oct 18;366(6463). pii: eaar5551. doi:
10.1126/science.aar5551. PubMed PMID: 31624181.


2: Hisano Y, Kono M, Cartier A, Engelbrecht E, Kano K, Kawakami K, Xiong Y, Piao
W, Galvani S, Yanagida K, Kuo A, Ono Y, Ishida S, Aoki J, Proia RL, Bromberg JS,
Inoue A, Hla T. Lysolipid receptor cross-talk regulates lymphatic endothelial
junctions in lymph nodes. J Exp Med. 2019 Jul 1;216(7):1582-1598. doi:
10.1084/jem.20181895. Epub 2019 May 30. PubMed PMID: 31147448; PubMed Central
PMCID: PMC6605750.


3: Obinata H, Hla T. Sphingosine 1-phosphate and inflammation. Int Immunol. 2019
Aug 23;31(9):617-625. doi: 10.1093/intimm/dxz037. PubMed PMID: 31049553; PubMed
Central PMCID: PMC6939830.


4: Xiong Y, Piao W, Brinkman CC, Li L, Kulinski JM, Olivera A, Cartier A, Hla T,
Hippen KL, Blazar BR, Schwab SR, Bromberg JS. CD4 T cell sphingosine 1-phosphate
receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic
migration. Sci Immunol. 2019 Mar 15;4(33). pii: eaav1263. doi:
10.1126/sciimmunol.aav1263. PubMed PMID: 30877143; PubMed Central PMCID:
PMC6744614.


5: Hisano Y, Hla T. Bioactive lysolipids in cancer and angiogenesis. Pharmacol
Ther. 2019 Jan;193:91-98. doi: 10.1016/j.pharmthera.2018.07.006. Epub 2018 Jul
23. Review. PubMed PMID: 30048709; PubMed Central PMCID: PMC6309747.


6: Yanagida K, Hla T. A dark side to omega-3 fatty acids. Nature. 2017 Dec
14;552(7684):180-181. doi: 10.1038/d41586-017-07678-8. PubMed PMID: 29239390;
PubMed Central PMCID: PMC6239194.


7: Kono M, Conlon EG, Lux SY, Yanagida K, Hla T, Proia RL. Bioluminescence
imaging of G protein-coupled receptor activation in living mice. Nat Commun. 2017
Oct 27;8(1):1163. doi: 10.1038/s41467-017-01340-7. PubMed PMID: 29079828; PubMed
Central PMCID: PMC5660082.



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of Harvard College