The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways
Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this pr...
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2025-01-01
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| author | Ahmed S. Elshikha Georges Abboud Rigena Avdiaj Laurence Morel Sihong Song |
| author_facet | Ahmed S. Elshikha Georges Abboud Rigena Avdiaj Laurence Morel Sihong Song |
| author_sort | Ahmed S. Elshikha |
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| description | Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing may represent a novel strategy to inhibit TLR-mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on endosomal TLRs remains elusive. In this study, we first tested the effect of hAAT on TLR9 signaling in dendritic cells (DCs). We showed that hAAT inhibited TLR9-mediated DC activation and cytokine production. Human AAT also lowered the expressions of interferon signature genes. Western blot analysis showed that hAAT reduced the expression of the active form (cleaved) of TLR9 in DCs, indicating a novel mechanism of hAAT function in the immune system. We next tested the effect of hAAT on TLR7/8 signaling. Similar to the effect on TLR9 signaling, hAAT also inhibited R848 (TLR7 and 8 agonist)-induced DC activation and functions and lowered the expressions of interferon signature genes. Our in vivo studies using hAAT transgenic mice also showed that hAAT attenuated R848-induced pathogenesis. Specifically, hAAT completely blocked the R848 induction of germinal center T cells (GC T), B cells (GC B), and plasma cells (GC PCs), as well as T follicular T helper cells (T<sub>FH</sub>), which are all critical in lupus development. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight into the clinical application of hAAT. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-48cbb97bd90c4309b3652f718bde165f2025-01-24T13:24:57ZengMDPI AGBiomolecules2218-273X2025-01-011514310.3390/biom15010043The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling PathwaysAhmed S. Elshikha0Georges Abboud1Rigena Avdiaj2Laurence Morel3Sihong Song4Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USAEndosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing may represent a novel strategy to inhibit TLR-mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on endosomal TLRs remains elusive. In this study, we first tested the effect of hAAT on TLR9 signaling in dendritic cells (DCs). We showed that hAAT inhibited TLR9-mediated DC activation and cytokine production. Human AAT also lowered the expressions of interferon signature genes. Western blot analysis showed that hAAT reduced the expression of the active form (cleaved) of TLR9 in DCs, indicating a novel mechanism of hAAT function in the immune system. We next tested the effect of hAAT on TLR7/8 signaling. Similar to the effect on TLR9 signaling, hAAT also inhibited R848 (TLR7 and 8 agonist)-induced DC activation and functions and lowered the expressions of interferon signature genes. Our in vivo studies using hAAT transgenic mice also showed that hAAT attenuated R848-induced pathogenesis. Specifically, hAAT completely blocked the R848 induction of germinal center T cells (GC T), B cells (GC B), and plasma cells (GC PCs), as well as T follicular T helper cells (T<sub>FH</sub>), which are all critical in lupus development. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight into the clinical application of hAAT.https://www.mdpi.com/2218-273X/15/1/43systemic lupus erythematosus (SLE)inflammationtoll-like receptors (TLRs)human alpha-1 antitrypsin (hAAT) |
| spellingShingle | Ahmed S. Elshikha Georges Abboud Rigena Avdiaj Laurence Morel Sihong Song The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways Biomolecules systemic lupus erythematosus (SLE) inflammation toll-like receptors (TLRs) human alpha-1 antitrypsin (hAAT) |
| title | The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways |
| title_full | The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways |
| title_fullStr | The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways |
| title_full_unstemmed | The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways |
| title_short | The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways |
| title_sort | inhibitory effects of alpha 1 antitrypsin on endosomal tlr signaling pathways |
| topic | systemic lupus erythematosus (SLE) inflammation toll-like receptors (TLRs) human alpha-1 antitrypsin (hAAT) |
| url | https://www.mdpi.com/2218-273X/15/1/43 |
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