The inflammatory milieu in injured and healing islets is a decisive factor in the development of autoimmune diabetes and yet we know very little about this milieu or how it contributes to immune regulation. We have recently identified a pivotal role for hyaluronan (HA), a component of the extracellular matrix (ECM) of injured and healing tissues, in the function and stability of Foxp3+ regulatory T-cells (Treg), a T-cell subset critical to the maintenance of immune tolerance. The effect of HA on Treg depends on its size. High molecular weight HA (HMW-HA), found in healing tissues, promotes Treg survival and function. HMW-HA does this by crosslinking CD44 and substituting for IL-2 in the IL-2R signaling required by Treg for their viability and for production of the key immunoregulatory cytokine IL-10. Consistent with this, CD44-/- mice have unremitting inflammation in response to injury, fewer Treg, and make less IL-10. HMW-HA therefore functions as a tissue integrity signal that supports Treg in healing tissues. Low-molecular weight HA (LMW-HA), characteristic of chronically inflamed tissues, inhibits Treg function and suppresses production of IL-10. LMW-HA is a Toll like receptor 2 (TLR2) ligand;LMW-HA may negatively regulate Treg function at sites of sterile inflammation in the same way that microbial TLR2 ligands are known to inhibit Treg at sites of active infection. Together, our data support a model whereby HA catabolism and signaling through CD44 and TLR2 link inflammation to Treg function at sites of sterile injury. If this model is correct, it may be possible to enhance Treg function, promote wound healing and prevent autoimmunity by supporting HA integrity. In vivo HA integrity is maintained by TSG-6 and other HA-binding molecules (hyaladherins) that covalently link HA strands. This prevents their degradation and promotes interactions with CD44. TSG-6 has been used experimentally to treat sepsis and other forms of inflammation but its value in autoimmunity is unknown. Here, we will elucidate the mechanisms by which HMW-HA and LMW-HA govern Treg behavior and determine what role HA integrity plays in Treg function in vivo using mouse models of autoimmune diabetes. The expected outcomes of these studies are a working knowledge of the mechanisms that govern immune regulation in injured and healing tissues and innovative, ECM-based strategies to promote wound healing and prevent autoimmunity.

Public Health Relevance

The proposed studies will greatly advance our understanding of the mechanisms that govern immune regulation in injured and healing pancreatic islets and will open the doors to innovative strategies to prevent autoimmune diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK096087-04
Application #
8728846
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Gebe, John A; Yadava, Koshika; Ruppert, Shannon M et al. (2016) Modified High Molecular Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance. Am J Respir Cell Mol Biol :
Kuipers, Hedwich F; Rieck, Mary; Gurevich, Irina et al. (2016) Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization. Proc Natl Acad Sci U S A 113:1339-44
Kuipers, H F; Nagy, N; Ruppert, S M et al. (2016) The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice. Clin Exp Immunol 185:372-81
Balaji, Swathi; King, Alice; Marsh, Emily et al. (2015) The role of interleukin-10 and hyaluronan in murine fetal fibroblast function in vitro: implications for recapitulating fetal regenerative wound healing. PLoS One 10:e0124302
Nagy, Nadine; Kaber, Gernot; Johnson, Pamela Y et al. (2015) Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis. J Clin Invest 125:3928-40
Balaji, Swathi; Han, Nate; Moles, Chad et al. (2015) Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds. Surgery 158:846-56
Ruppert, Shannon M; Falk, Ben A; Long, S Alice et al. (2015) Regulatory T Cells Resist Cyclosporine-Induced Cell Death via CD44-Mediated Signaling Pathways. Int J Cell Biol 2015:614297
Nagy, Nadine; Kuipers, Hedwich F; Frymoyer, Adam R et al. (2015) 4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Front Immunol 6:123
Ruppert, S M; Hawn, T R; Arrigoni, A et al. (2014) Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation. Immunol Res 58:186-92
Balaji, Swathi; Moles, Chad M; Bhattacharya, Sukanta S et al. (2014) Comparison of interleukin 10 homologs on dermal wound healing using a novel human skin ex vivo organ culture model. J Surg Res 190:358-66

Showing the most recent 10 out of 18 publications