Abstract
Neurodegenerative diseases are a set of disorders characterized by progressive neuronal death and are associated with microglia-mediated neuroinflammation. Recently, neuroinflammation is proposed as a promising therapeutic target for many neurodegenerative diseases. Alpha-1 antitrypsin (AAT) is recognized as a novel immunomodulatory agent in autoimmune diseases and transplantation, however, its impact on neuroinflammation and neurodegeneration remains unknown. This study aims to explore the effects of AAT on microglia-mediated neuroinflammation and retinal degeneration in rd1 mouse model. We found reduced expression of AAT in rd1 retina, and AAT supplement exhibited certain protective effect on retinal degeneration, presenting with increased amount of photoreceptor nuclei, and amplified wave amplitudes in electroretinogram analysis. Of note, AAT shifted microglia phenotype from pro-inflammatory M1 (CD16/CD32+, iNOS+) to anti-inflammatory M2 (CD206+, Arg1+) both in vivo and in vitro, underscoring the concept of immunomodulation on microglia polarization by AAT during neurodegeneration. Furthermore, AAT suppressed the activation of STAT1, promoted the expression of IRF4 while inhibited IRF8 expression, indicating the involvement of these signaling pathways in AAT immunomodulation. Collectively, our data provided evidence for a novel protective role of AAT through immunomodulation on microglia polarization. Attenuating neuroinflammation by AAT may be beneficial to retard neurodegeneration in rd1 mice.
Highlights
Neurodegenerative diseases are a heterogeneous group of disorders characterized by progressive loss of specific neurons and association with neuroinflammation
Alpha-1 antitrypsin (AAT) is mainly produced by hepatocytes, it could derive from macrophages, monocytes, and other cells [21, 22]
Decreased expression of AAT was observed in rd1 retina as the disease progressed from P4 to P20 and its expression reduced markedly compared with the same age C57 controls, whereas both mice presented similar levels of AAT at P4 (Figures 1E,F)
Summary
Neurodegenerative diseases are a heterogeneous group of disorders characterized by progressive loss of specific neurons and association with neuroinflammation. Retinitis pigmentosa (RP), one of the most common inherited retinal degeneration, is a major cause of incurable vision loss [1]. It is a highly complex neurodegenerative disease defined by progressive degeneration of photoreceptors or retinal pigment epithelium (RPE) caused by various mutations [2]. More than 200 mutant genes have been identified [3, 4] and gene therapy faces the challenge of genetic heterogeneity, Abbreviations: AAT, alpha-1 antitrypsin; RP, retinitis pigmentosa; RPE, retinal pigment epithelium; ERG, electroretinogram; OCT, optical coherence tomography; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; CNS, central nervous system; IRF, interferon-regulatory factor. Drugs that target on the broad biological processes which are common across various mutations in RP may show some efficacy in this complicated disorder [6]
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