Novel AHR ligand AGT-5 ameliorates type 1 diabetes in mice through regulatory cell activation in the early phase of the disease
2024
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Аутори:
Jonić, NatalijaKoprivica, Ivan
Kyrkou, Stavroula G
Bistas, Vasileios-Panagiotis
Chatzigiannis, Christos
Radulović, Nataša
Pilipović, Ivan
Jovanović, Anđelina
Jovanović, Milan B.
Dimitrijević, Mirjana
Tzakos, Andreas G
Stojanović, Ivana D.
Тип документа:
Чланак у часопису (Објављена верзија)
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© 2024 Jonić , Koprivica, Kyrkou, Bistas, Chatzigiannis, Radulović , Pilipović , Jovanović , Jovanovic , Dimitrijević , Tzakos and Stojanović
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Приказ свих података о документуАпстракт:
Type 1 diabetes (T1D) is an autoimmune disease with a strong chronic
inflammatory component. One possible strategy for the treatment of T1D is to
stimulate the regulatory arm of the immune response, i.e. to promote the
function of tolerogenic dendritic cells (tolDC) and regulatory T cells (Treg).
Since both cell types have been shown to be responsive to the aryl
hydrocarbon receptor (AHR) activation, we used a recently characterized
member of a new class of fluorescent AHR ligands, AGT-5, to modulate
streptozotocin-induced T1D in C57BL/6 mice. Prophylactic oral administration
of AGT-5 reduced hyperglycemia and insulitis in these mice. Phenotypic and
functional analysis of cells in the pancreatic infiltrates of AGT-5-treated mice (at
the early phase of T1D) revealed a predominantly anti-inflammatory
environment, as evidenced by the upregulation of tolDC and Treg frequency,
while CD8+ cell, Th1 and Th17 cells were significantly reduced. Similarly, AGT-5
enhanced the proportion of Treg and tolDC in small intestine lamina propria and
suppressed the activation status of antigen-presenting cells through downregulation of co-stimulatory molecules CD40, CD80 and CD86. The
expression levels of Cyp1a1, controlled by the AHR, were increased in CD4+,
CD8+ and Treg, confirming the AHR-mediated effect of AGT-5 in these cells.
Finally, AGT-5 stimulated the function of regulatory cells in the pancreatic islets
and lamina propria by upregulating indoleamine 2,3-dioxigenase 1 (IDO1) in
tolDC. These findings were supported by the abrogation of AGT-5-mediated in
vitro effects on DC in the presence of IDO1 inhibitor. AGT-5 also increased the
expression of CD39 or CD73 ATP-degrading ectoenzymes by Treg. The increase
in Treg is further supported by the upregulated frequency of IL-2-producing type
3 innate lymphoid cells (ILC3) in the lamina propria. Anti-inflammatory effects of
AGT-5 were also validated on human tonsil cells, where in vitro exposure to AGT-
5 increased the proportion of immunosuppressive dendritic cells and ILC3. These results suggest that AGT-5, by stimulating AHR, may promote a general
immunosuppressive environment in the pancreas and small intestine lamina
propria at the early phase of disease, and thereby inhibit the severity of T1D
in mice.
Кључне речи:
type 1 diabetes (T1D); aryl hydrocarbon receptor (AhR); T regulatory cell (TREG); insulitis; gut-associated lymphoid tissue (GALT); lamina propriaИзвор:
Frontiers in Immunology, 2024, 15, 1454156-Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
- European Regional Development Fund of the European Union
- Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH-CREATE-INNOVATE (project code: TAEDK-06189/T2EDK-0326, Acronym: Glioblastoma)