Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles

Abstract

Neuroinflammation, blood-brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute-phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well-cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible interpretations for previously controversial data and present perspectives regarding the potential role of Serpina3n/SERPINA3 in CNS pathologies, including demyelinating disorders where oligodendrocytes are the primary targets. We hypothesise that the 'good' or 'bad' aspects of Serpina3n/SERPINA3 depend on its cellular sources, its subcellular distribution (or mis-localisation) and/or disease/injury types. Furthermore, circulating Serpina3n/SERPINA3 may cross the BBB to impact CNS pathologies. Cell-specific genetic tools are critically important to tease out the potential roles of cell type-dependent Serpina3n in CNS diseases/injuries.

Keywords: Serpina3n/SERPINA3; blood–brain barrier; cell death/survival; multiple sclerosis; myelin; neuroinflammation; neurological disease/injury; neuron/glia.

Figure 1 –

acute response of Serpina3n in the liver to LPS-induced systemic inflammation. A, Western blot assay of Serpina3n and Albumin (produced solely by hepatocytes) in the mouse liver of PBS control and Day 1 and Day 3 after single LPS i.p. injection. B, ELISA assay of serum Serpina3n level in treated mice. A single dose of 5 mg/kg of the endotoxin LPS from Escherichia coli O55:B55 (Sigma-Aldrich) (dissolved in PBS) was injected into postnatal day 35-old mice (Zamanian et al., 2012).

Figure 2 –

Serpina3n expression in postnatal homeostatic murine brain. A-B. Single cell RNA-seq [90] showing low yet detectable level of Serpina3n mRNA in oligodendroglial lineage cells (A) whose abundance is equivalent to that of the key transcription factor for oligodendrocyte maturation Sp7 (B)[36]. C, immunofluorescence staining of Serpina3n and neuronal marker HuC/D. Very intense cytoplasmic Serpina3n was observed in the neurons (HuC/D+) at the basal-medial nuclei of the hypothalamus around the brain third ventricle (3V).

Figure 3 –

Astrocytic end-feet wrap Serpina3n⁺ blood vessel structures in the brain after 24 hours of a single dose of systemic LPS injection to P35 old mice. Images were taken from the dorsal cortex of the forebrain.

Figure 4 –. hypothetical roles of Serpina3n/SERPINA3 in CNS pathologies.

We use LPS-induced inflammation and BBB disruption as an example for illustrating the hypothetical role of Serpina3n/SERPINA3 since brain inflammation and BBB leakage are common pathologies in various neurological disorders and injuries. 1, liver hepatocytes rapidly upregulate and secrete Serpina3n into the bloodstream (cf Fig. 1) in responses to LPS stimulation. 2, Serpina3n, together with other acute phase inflammatory molecules (such as TNFa, IL1b), may induce vascular inflammation, which, in turn, upregulates Serpina3n expression in vascular cells (cf Fig. 3). 3, the peripheral derived Serpina3n may affect BBB permeability and presumable leakage into the brain parenchyma during brain diseases and injuries. 4 and 5, Serpina3n may play a role in transforming resting microglia (MG) into activated microglia/macrophages and quiescent astrocytes (Astro) into reactive astrocytes (RAs), and augmenting brain inflammation. 6, neuronal/axonal dysfunction and OL/myelin damage are commonly observed in neurological disorders and injuries. 7, RAs and dying neurons have been shown to dysregulate Serpina3n in a disease/injury type-dependent manner. Recent data suggest that injured/damaged OLs (referred to as reactive oligodendrocytes, ROs) are a primary cell population displaying Serpina3n dysregulation. Serpina3n is secreted into the extracellular space, presumably from ROs, RAs, and/or injured neurons, and may also be derived from peripheral organs as well. 8, it remains enigmatic whether extracellular Serpina3n affects BBB permeability and the activation/function of microglia and astrocytes in a paracrine manner in the inflamed CNS. 9, it is also elusive if abnormal accumulation and mis-localization of Serpina3n in the cytosol in reactive OLs, RAs, or dying neurons regulate the survival or death of their own cell populations in an autocrine manner in various CNS pathologies, such as MS, AD, brain injury and normal ageing.