Immunoproteasomal Processing of IsoLG-Adducted Proteins Is Essential for Hypertension
BACKGROUND: Hypertension is characterized by CD8+ T cell activation and infiltration into peripheral tissues. CD8+ T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome. We hypothesized that immunoproteasomal processing of isoLG-adducts is essential for CD8+ T cell activation and inflammation in hypertension.
METHODS: IsoLG adduct processing was studied in murine dendritic cells (DCs), endothelial cells (ECs), and B8 fibroblasts. The role of the proteasome and the immunoproteasome in Ang II (angiotensin II)-induced hypertension was studied in C57BL/6 mice treated with bortezomib or the immunoproteasome inhibitor PR957 and by studying mice lacking 3 critical immunoproteasome subunits (triple knockout mouse). We also examined hypertension in mice lacking the critical immunoproteasome subunit LMP7 specifically in either DCs or ECs.
RESULTS: We found that oxidant stress increases the presence of isoLG adducts within MHC-I (class I major histocompatibility complex), and immunoproteasome overexpression augments this. Pharmacological or genetic inhibition of the immunoproteasome attenuated hypertension and tissue inflammation. Conditional deletion of LMP7 in either DCs or ECs attenuated hypertension and vascular inflammation. Finally, we defined the role of the innate immune receptors stimulator of interferon genes and TLR7/8 (toll-like receptor 7/8) as drivers of LMP7 expression in ECs.
CONCLUSIONS: These studies define a previously unknown role of the immunoproteasome in DCs and ECs in CD8+ T cell activation. The immunoproteasome in DCs and ECs is critical for isoLG-adduct presentation to CD8+ T cells, and in the endothelium, this guides homing and infiltration of T cells to specific tissues.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
Circulation research - (2024) vom: 16. Apr. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
de la Visitación, Néstor [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Dendritic cell |
|---|
| Anmerkungen: |
Date Revised 16.04.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1161/CIRCRESAHA.124.324068 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM371128838 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM371128838 | ||
| 003 | DE-627 | ||
| 005 | 20240416233717.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240416s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCRESAHA.124.324068 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1377.xml |
| 035 | |a (DE-627)NLM371128838 | ||
| 035 | |a (NLM)38623763 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a de la Visitación, Néstor |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Immunoproteasomal Processing of IsoLG-Adducted Proteins Is Essential for Hypertension |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 16.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a BACKGROUND: Hypertension is characterized by CD8+ T cell activation and infiltration into peripheral tissues. CD8+ T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome. We hypothesized that immunoproteasomal processing of isoLG-adducts is essential for CD8+ T cell activation and inflammation in hypertension | ||
| 520 | |a METHODS: IsoLG adduct processing was studied in murine dendritic cells (DCs), endothelial cells (ECs), and B8 fibroblasts. The role of the proteasome and the immunoproteasome in Ang II (angiotensin II)-induced hypertension was studied in C57BL/6 mice treated with bortezomib or the immunoproteasome inhibitor PR957 and by studying mice lacking 3 critical immunoproteasome subunits (triple knockout mouse). We also examined hypertension in mice lacking the critical immunoproteasome subunit LMP7 specifically in either DCs or ECs | ||
| 520 | |a RESULTS: We found that oxidant stress increases the presence of isoLG adducts within MHC-I (class I major histocompatibility complex), and immunoproteasome overexpression augments this. Pharmacological or genetic inhibition of the immunoproteasome attenuated hypertension and tissue inflammation. Conditional deletion of LMP7 in either DCs or ECs attenuated hypertension and vascular inflammation. Finally, we defined the role of the innate immune receptors stimulator of interferon genes and TLR7/8 (toll-like receptor 7/8) as drivers of LMP7 expression in ECs | ||
| 520 | |a CONCLUSIONS: These studies define a previously unknown role of the immunoproteasome in DCs and ECs in CD8+ T cell activation. The immunoproteasome in DCs and ECs is critical for isoLG-adduct presentation to CD8+ T cells, and in the endothelium, this guides homing and infiltration of T cells to specific tissues | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a dendritic cell | |
| 650 | 4 | |a endothelial cell | |
| 650 | 4 | |a hypertension | |
| 650 | 4 | |a immunoproteasome | |
| 650 | 4 | |a isolevuglandin | |
| 700 | 1 | |a Chen, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Krishnan, Jaya |e verfasserin |4 aut | |
| 700 | 1 | |a Van Beusecum, Justin P |e verfasserin |4 aut | |
| 700 | 1 | |a Amarnath, Venkataraman |e verfasserin |4 aut | |
| 700 | 1 | |a Hennen, Elizabeth M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Shilin |e verfasserin |4 aut | |
| 700 | 1 | |a Saleem, Mohammad |e verfasserin |4 aut | |
| 700 | 1 | |a Ao, Mingfang |e verfasserin |4 aut | |
| 700 | 1 | |a Dikalov, Sergey I |e verfasserin |4 aut | |
| 700 | 1 | |a Dikalova, Anna E |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, David G |e verfasserin |4 aut | |
| 700 | 1 | |a Patrick, David M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation research |d 1953 |g (2024) vom: 16. Apr. |w (DE-627)NLM000001910 |x 1524-4571 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:16 |g month:04 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1161/CIRCRESAHA.124.324068 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 16 |c 04 | ||