Roles of Alpha-1 Antitrypsin in Human Health and Disease Models

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 15 September 2025 | Viewed by 1539

Special Issue Editor


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Guest Editor
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
Interests: functions and applications of alpha-1 antitrypsin (AAT) and SERPIN; development of novel treatment for autoimmune and inflammatory diseases; gene therapy using recombinant adeno-associated viral vectors (rAAV)

Special Issue Information

Dear Colleagues,

Alpha-1 antitrypsin (AAT), a member of serine proteinase inhibitor (SERPIN) superfamily, has multiple functions including the inhibition of proteinases and the regulation of immune system. As a proteinase inhibitor, AAT can reduce tissue damage and degeneration, which is commonly involved in autoimmune and inflammatory diseases. AAT can also interact with immune regulatory molecules and mediate anti-inflammatory effects. Studies have shown that AAT has the therapeutic potential for the treatment of human diseases including AAT deficiency (AATD), graft-versus-host disease (GvHD), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and COVID-19. However, the mechanism(s) underlying the therapeutic effects of AAT remain elusive. In addition, AAT may have unknown functions to be further investigated. This Specific Issue aims to publish recent findings that advance the therapeutic applications and the functional mechanism(s) of AAT and related molecules.

Prof. Dr. Sihong Song
Guest Editor

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Keywords

  • alpha-1 antitrypsin
  • serine proteinase inhibitor (SERPIN)
  • autoimmunity
  • inflammation
  • aging
  • cancer

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Published Papers (1 paper)

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Research

14 pages, 2405 KiB  
Article
The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways
by Ahmed S. Elshikha, Georges Abboud, Rigena Avdiaj, Laurence Morel and Sihong Song
Biomolecules 2025, 15(1), 43; https://doi.org/10.3390/biom15010043 - 1 Jan 2025
Viewed by 1070
Abstract
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 [...] Read more.
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 (TFH), 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. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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