Prokineticin‐2 promotes chemotaxis and alternative A2 reactivity of astrocytes

Abstract

Astrocyte reactivity is disease- and stimulus-dependent, adopting either a pro-inflammatory A1 phenotype or a protective, anti-inflammatory A2 phenotype. Recently, we demonstrated, using cell culture, animal models and human brain samples, that dopaminergic neurons produce and secrete higher levels of the chemokine-like signaling protein Prokineticin-2 (PK2) as a compensatory protective response against neurotoxic stress. Since astrocytes express a high level of PK2 receptors, herein, we systematically characterize the role of PK2 in astrocyte structural and functional properties. PK2 treatment greatly induced astrocyte migration, which was accompanied by a shift in mitochondrial energy metabolism, a reduction in pro-inflammatory factors, and an increase in the anti-oxidant genes Arginase-1 and Nrf2. Overexpression of PK2 in primary astrocytes or in the in vivo mouse brain induced the A2 astrocytic phenotype with upregulation of key protective genes and A2 reactivity markers including Arginase-1 and Nrf2, PTX3, SPHK1 and TM4SF1. A small molecule PK2 agonist IS20 not only mimicked the protective effect of PK2 in primary cultures, but also increased glutamate uptake by upregulating GLAST. Notably, IS20 blocked not only MPTP-induced reductions in the A2 phenotypic markers SPHK1 and SCL10a6 but also elevation of the of A1 marker GBP2. Collectively, our results reveal that PK2 regulates a novel neuron-astrocyte signaling mechanism by promoting an alternative A2 protective phenotype in astrocytes, which could be exploited for development of novel therapeutic strategies for PD and other related chronic neurodegenerative diseases.

Cellular infiltration in traumatic brain injury

“…Recently, Neal et al [ 162 ] discovered that PK2(prokineticin 2)-induced astrocyte reactivity leads to an increase in antioxidant and anti-inflammatory proteins with increasing glutamate uptake resulting in decreased inflammatory factors. Furthermore, Ma and colleagues [ 163 ] whilst working on SAH (subarachnoid haemorrhage)-induced early brain injury added that administration of rPK2 (recombinant PK2) or augmenting PK2 expression may stimulate a modulation of astrocytic polarisation towards a more protective (A2-type) phenotype.…”

Optogenetic manipulation of astrocytes from synapses to neuronal networks: A potential therapeutic strategy for neurodegenerative diseases

“…In that case, selectively killing or reprogramming harmful activated astrocytes, and increasing the number of beneficial activated astrocytes, may also be effective approaches to ameliorate NDs. The proinflammatory effect of A1 has been confirmed in many studies (Clark et al, 2019;Li et al, 2018;Wang et al, 2018;Yun et al, 2018;Zou et al, 2019), while A2 is relatively few (Atsushi et al, 2018;Neal et al, 2018). Given that the hypothesis of two types of astrocyte is based on a single animal model, do these two subtypes play the same role in different diseases?…”

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…A recent study showed that activated (pro-in ammatory) microglia induce a neurotoxic A1 subtype of astrocytes, which secrete a currently unknown neurotoxin that results in neuronal cell death (48). A1 astrocytes can be discriminated from the neuroprotective A2 astrocytes not only by the upregulation of genetic markers (47)(48)(49)55), but also by distinct morphological changes, which appear to be similar to those of microglia during neuroin ammation (56). While retraction of astrocytic processes, hypertrophy and gliosis has been described for astrocytes under various conditions (57), no study -to the best of our knowledge -comprehensively addressed alterations in astrocyte morphology during chronic neuroin ammation using a three-dimensional reconstruction pro ler.…”