The VGF-derived Peptide TLQP21 Impairs Purinergic Control of Chemotaxis and Phagocytosis in Mouse Microglia

Abstract

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 ϩ 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 2ϩ 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.

Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease

“…Indeed, the data presented here are consistent with causal roles for TLQP-62 and the VGF proprotein in AD pathogenesis and progression, but do not rule out contributions of other VGF-derived peptides including TLQP-21, an activator of the C3aR1 complement receptor 66 . Of note, we and others have recently shown that TLQP-21 reduces neuropathology in male 5xFAD mice and increases amyloid uptake in transformed BV2 mouse microglia and in primary cultured mouse microglia via a C3aR1-dependent pathway [87][88][89] , consistent with the previous identification of a critical complement network module in AD 5 .…”

Understanding microglial diversity and implications for neuronal function in health and disease

“…Mice that lack MER and AXL specifically in microglia accumulate neuronal progenitor cells in the subventricular zone, and this phagocytotic process seems to driven by TAM receptor ligands Gas6 and Protein S (Fourgeaud et al., 2016 ). Importantly, microglial phagocytosis concurs with the upregulation of a unique neurogenic secretome (i.e., VGF, VEGF, FGF2), potentially suggesting a feedback loop for neurogenesis (Diaz‐Aparicio et al., 2020 ; Elmadany et al., 2020 ). Alternative to phagocytosis, hippocampal microglia contribute to neuronal cell death via CR3‐DAP12‐dependent production of superoxide ions (Wakselman et al., 2008 ).…”

Histamine triggers microglial responses indirectly via astrocytes and purinergic signaling

“…Hrh 2 (and also P2ry12 ) receptors are known to be linked to cAMP signaling pathways, and not‐like Hrh1 ‐ to Ca 2+ . However, it has been previously observed that GPCRs linked to G i or G s proteins can also elicit intracellular Ca 2+ elevations (Elmadany, de Almeida Sassi, et al, 2020; Kuhn et al, 2004; Pannell et al, 2014), potentially by signaling of the Gßɤ subunits in a PLC/IP 3 R‐dependent fashion from internal stores (Clapham, 2007). Ca 2+ elevations downstream of Hrh2 (Esbenshade et al, 2003) or P2ry12 (De Simone et al, 2010; Irino et al, 2008; Jiang et al, 2017; Pausch et al, 2004) activation were previously demonstrated.…”