Mechanisms of immune modulation mediated by Mesencephalic Astrocyte-derived Neurotrophic Factor
Year: 2022
Type: dissertation
Abstract: Aging is characterized by a progressive decline in tissue function and integrity and an overall decline in regenerative potential. This reduction can be attributed to stem cell intrinsic dysfunctions and alterations in the local and systemic environments, including age-related immune dysfunction. The skeletal muscle is a paradigmatic model to study age-associated loss of regenerative capacity. Muscle repair depends on the precise coordination between myogenesis and the immune response and relies on the balance between pro- and anti-inflammatory signalling. Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an evolutionarily conserved protein with immunomodulatory and tissue repair functions. MANF is widely expressed in the body and was found to be transiently induced during skeletal muscle regeneration, particularly by pro-repair macrophages. However, its levels are downregulated during aging, which is associated with impairments in muscle regeneration and immune responses. In the present study, we intend to investigate the role of MANF in the process of immune modulation during skeletal muscle regeneration. Here, we demonstrate that organismal MANF loss results in a severe regenerative failure with accumulation of necrotic fibres and failure in myofibers formation. Ubiquitous loss of MANF disrupts the immune response to damage, affecting myeloid accumulation, macrophages transition towards a pro-repair state, bone marrow emergency hematopoiesis and the numbers of circulating monocytes. We further explore the specific role of MANF on macrophages, identifying a potential autocrine function in the phenotypic transition of macrophage subpopulations. In addition, we uncover intrinsic alterations in pro-repair macrophages with MANF ablation that can be associated with defective digestion of cellular debris. This work demonstrates how a systemic immune modulator can regulate the immune response to tissue damage at multiple levels, including in the production of myeloid cells and locally during the regenerative process.
Author: Brás, Maria Margarida Ferreira
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7048709974