TY - JOUR
T1 - The VGF-derived Peptide TLQP21 Impairs Purinergic Control of Chemotaxis and Phagocytosis in Mouse Microglia
AU - Elmadany, Nirmeen
AU - de Almeida Sassi, Felipe
AU - Wendt, Stefan
AU - Logiacco, Francesca
AU - Visser, Josien
AU - Haage, Verena
AU - Hernandez, Daniel Perez
AU - Mertins, Philipp
AU - Hambardzumyan, Dolores
AU - Wolf, Susanne
AU - Kettenmann, Helmut
AU - Semtner, Marcus
N1 - Funding Information:
This work was supported by Deutsche Forschungsgemeinschaft SFB TRR43, EXC 257 NeuroCure, Helmholtz-Gemeinschaft, Zukunftsthema Immunology and Inflammation ZT-0027, and Einstein-Stiftung. N.E. was supported by a Deutscher Akademischer Austauschdienst scholarship. We thank the Advanced Light Microscopy facility of the Max-Delbrück-CenterBerlin-BuchfortechnicalassistancewithconfocalmicroscopyandImaris-baseddataanalysis.
Publisher Copyright:
Copyright © 2020 the authors
PY - 2020/4/22
Y1 - 2020/4/22
N2 - Microglial cells are considered as sensors of brain pathology by detecting any sign of brain lesions, infections, or dysfunction and can influence the onset and progression of neurological diseases. They are capable of sensing their neuronal environment via many different signaling molecules, such as neurotransmitters, neurohormones and neuropeptides. The neuropeptide VGF has been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide and has been shown to signal via C3aR1 and C1qBP receptors. The effect of TLQP21 on microglial functions in health or disease is not known. Studying microglial cells in acute brain slices, we found that TLQP21 impaired metabotropic purinergic signaling. Specifically, it attenuated the ATP-induced activation of a K +conductance, the UDP-stimulated phagocytic activity, and the ATP-dependent laser lesion-induced process outgrowth. These impairments were reversed by blocking C1qBP, but not C3aR1 receptors. While microglia in brain slices from male mice lack C3aR1 receptors, both receptors are expressed in primary cultured microglia. In addition to the negative impact on purinergic signaling, we found stimulating effects of TLQP21 in cultured microglia, which were mediated by C3aR1 receptors: it directly evoked membrane currents, stimulated basal phagocytic activity, evoked intracellular Ca 2 + transient elevations, and served as a chemotactic signal. We conclude that TLQP21 has differential effects on microglia depending on C3aR1 activation or C1qBP-dependent attenuation of purinergic signaling. Thus, TLQP21 can modulate the functional phenotype of microglia, which may have an impact on their function in health and disease.
AB - Microglial cells are considered as sensors of brain pathology by detecting any sign of brain lesions, infections, or dysfunction and can influence the onset and progression of neurological diseases. They are capable of sensing their neuronal environment via many different signaling molecules, such as neurotransmitters, neurohormones and neuropeptides. The neuropeptide VGF has been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide and has been shown to signal via C3aR1 and C1qBP receptors. The effect of TLQP21 on microglial functions in health or disease is not known. Studying microglial cells in acute brain slices, we found that TLQP21 impaired metabotropic purinergic signaling. Specifically, it attenuated the ATP-induced activation of a K +conductance, the UDP-stimulated phagocytic activity, and the ATP-dependent laser lesion-induced process outgrowth. These impairments were reversed by blocking C1qBP, but not C3aR1 receptors. While microglia in brain slices from male mice lack C3aR1 receptors, both receptors are expressed in primary cultured microglia. In addition to the negative impact on purinergic signaling, we found stimulating effects of TLQP21 in cultured microglia, which were mediated by C3aR1 receptors: it directly evoked membrane currents, stimulated basal phagocytic activity, evoked intracellular Ca 2 + transient elevations, and served as a chemotactic signal. We conclude that TLQP21 has differential effects on microglia depending on C3aR1 activation or C1qBP-dependent attenuation of purinergic signaling. Thus, TLQP21 can modulate the functional phenotype of microglia, which may have an impact on their function in health and disease.
KW - C1qBP
KW - C3aR1
KW - Microglia
KW - Purinergic signaling
KW - TLQP21
KW - VGF
UR - http://www.scopus.com/inward/record.url?scp=85083713953&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1458-19.2020
DO - 10.1523/JNEUROSCI.1458-19.2020
M3 - Article
C2 - 32060170
AN - SCOPUS:85083713953
SN - 0270-6474
VL - 40
SP - 3320
EP - 3331
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 17
ER -