Abstract
Regeneration is an important process in multicellular organisms, responsible for homeostatic renewal and repair of different organs after injury. Immune cell activation is observed at early stages of the regenerative response and its regulation is essential for regenerative success. Thus, immune regulators play central roles in optimizing regenerative responses. Neurotrophic factors (NTFs) are secreted molecules, defined by their ability to support neuronal cell types. However, emerging evidence suggests that they can also play important functions in the regulation of immune cell activation and tissue repair. Here we discuss the literature supporting a role of NTFs in the regulation of inflammation and regeneration. We will focus, in particular, in the emerging roles of mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) in the regulation of immune cell function and in the central role that immune modulation plays in their biological activity in vivo. Finally, we will discuss the potential use of these factors to optimize regenerative success in vivo, both within and beyond the nervous system.
Highlights
Inflammatory and regenerative responses are tightly co-regulated during tissue repair (Aurora and Olson, 2014)
mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) were initially discovered by their neurotrophic activities, further studies revealed that MANF and CDNF are highly expressed in non-neural tissues and that their cytoprotective activity extends beyond the dopaminergic system (Tadimalla et al, 2008, Airavaara et al, 2009; Glembotski et al, 2012; Lindahl et al, 2014; Yang et al, 2014; Neves et al, 2016; Gao et al, 2017; Liu et al, 2018; Lu et al, 2018; Matlik et al, 2018)
Using in vitro assays on hemocytes isolated from Drosophila, or macrophages differentiated from bone marrow precursors from mice, we showed that both cell types respond to stimulation with recombinant MANF protein, activating a phenotypic switch and transcriptional profile associated with pro-reparative functions of macrophages
Summary
Inflammatory and regenerative responses are tightly co-regulated during tissue repair (Aurora and Olson, 2014). There are two main families of NTFs: neurotrophins, including Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrophin-3 (NT-3) and Neurotrophin-4 (NT-4); and glial cell-line derived neurotrophic factor family ligands (GFLs), of which Glial cell linederived neurotrophic factor (GDNF) is the most studied member (Airaksinen et al, 1999; Chao, 2003) Neurotrophins exert their trophic effects by signaling through tropomyosin-receptor kinase (Trk) receptor tyrosine kinases or by p75 neurotrophin receptor (p75NTR), a receptor that is shared by immune regulators, such as tumor necrosis factor (TNF) family cytokines (Chao, 2003). GFLs, on the other hand, signal through the transmembrane Ret receptor tyrosine kinase, and receptor activation is mediated by GDNF family receptor alpha-1 (GFRα1) (Airaksinen et al, 1999) These receptors have functions outside the nervous system, including in hematopoietic stem cells and immune cells (Fonseca-Pereira et al, 2014; Ibiza et al, 2016). We will focus in particular in the emerging functions of MANF and CDNF and speculate on their potential to act as pro-repair factors in regenerative systems beyond the nervous system
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