Complement 3a receptor in dorsal horn microglia mediates pronociceptive neuropeptide signaling

Doolen, Suzanne; Cook, Jack; Riedl, Maureen; Kitto, Kelley F.; Kohsaka, Shinichi; Honda, Christopher N.; Fairbanks, Carolyn A.; Taylor, Bradley K.; Vulchanova, Lucy

doi:10.1002/glia.23208

Cited by 32 publications

(54 citation statements)

References 55 publications

(81 reference statements)

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“…This suggests an essential role for microglial C3aR1 in the communication between neurons, astrocytes, and microglia. In another example of such communication between cell types, TLQP-21 has a dose-dependent pronociceptive effect in spinal cord through the activation of dorsal horn microglia in the spared nerve injury (SNI) model of neuropathic pain [47,73]. VGF expression is induced in dorsal root ganglion (DRG) neurons within 24 h of injury and persists for at least 7 days, and VGF-derived peptides, including TLQP-21, may contribute to the development and maintenance of nerve injury induced hypersensitivity [73,74].…”

Section: Discussionmentioning

confidence: 99%

“…VGF expression is induced in dorsal root ganglion (DRG) neurons within 24 h of injury and persists for at least 7 days, and VGF-derived peptides, including TLQP-21, may contribute to the development and maintenance of nerve injury induced hypersensitivity [73,74]. In fact, the pronociceptive effect of TLQP-21 is mediated by C3aR1-expressing microglia in the spinal cord [47]. TLQP-21 evokes Ca 2+ transients in microglia that is C3aR1-dependent and can be blocked by C3aR1 inhibitor or C3aR1 gene deletion, while both C3aR1 antagonist and TLQP-R21A reduced spinal nerve injuryinduced hypersensitivity in the mouse SNI model [47].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the pronociceptive effect of TLQP-21 is mediated by C3aR1-expressing microglia in the spinal cord [47]. TLQP-21 evokes Ca 2+ transients in microglia that is C3aR1-dependent and can be blocked by C3aR1 inhibitor or C3aR1 gene deletion, while both C3aR1 antagonist and TLQP-R21A reduced spinal nerve injuryinduced hypersensitivity in the mouse SNI model [47].…”

Section: Discussionmentioning

confidence: 99%

“…1b). We therefore used 1 μM concentrations, as previously used by others [47], for both peptides to characterize the effects of TLQP-21.…”

Section: Tlqp-21 Increases Bv2 Cell Migration and Phagocytotic Activitymentioning

confidence: 99%

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VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

Gaamouch

Audrain

Lin

et al. 2020

Mol Neurodegeneration

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Background: Multiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) identified VGF as a major driver of Alzheimer's disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression. Methods: We performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human. Results: We demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA-and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21. Conclusions: These data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…1b). We therefore used 1 μM concentrations, as previously used by others [47], for both peptides to characterize the effects of TLQP-21.…”

Section: Tlqp-21 Increases Bv2 Cell Migration and Phagocytotic Activitymentioning

confidence: 99%

See 2 more Smart Citations

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

Gaamouch

Audrain

Lin

et al. 2020

Mol Neurodegeneration

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“…While limited information is so far available regarding the pancreas immunolocalization of gC1q-R [26], C3aR1 is known to be expressed in human and mouse islets, within β-and α-cells [27] and to potentiate 5 glucose-induced insulin secretion from human and mouse islets [27]. Furthermore, C3a-R1, compared to gC1q-R, has been more studied as TLQP-21 receptor [13,28,29] and has been characterized in its precise reactivity depending on the C-terminal sequence of the TLQP-21 peptide [13]. We can hypothesize that TLQP-21, by returning to the pancreas from the plasma, could interact with the C3a-R1, in order to modulate the insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

Changes of TLQP-21 in Response to Glucose Load

Cocco

Corda

Noli

et al. 2019

Preprint

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5 The TLQP-21 peptide peripherally potentiates glucose-stimulated insulin secretion. The aim of this study was to investigate a possible endocrine mechanism through which TLQP-21 increases the insulin secretion. Using an antibody specific for the common N-terminal portion of the TLQP peptides, we studied pancreas and plasma of mice subjected to intraperitoneal glucose load, by immunohistochemistry and immunosorbent assay (ELISA), 10 alone or coupled to High Performance Liquid Chromatography (HLPC). Mice underwent a period of starvation hence have received a glucose load, or saline, and were sacrificed 30 or 120 minutes later. In normal endocrine pancreas, the TLQP-antiserum stained either peripheral or central cells. Interestingly, 30 min after a glucose load, TLQP immunostaining was disappeared in pancreas and, when analysed by ELISA, the TLQP-levels started to 15 increase in plasma reaching peak concentration at 120 min. (controls vs. 30 and 120 min.:p<0.05 and p<0.001, respectively). The analysis of plasma and pancreas extracts using HLPC coupled to ELISA demonstrated the presence of the TLQP-21, with statistically significant increase of this peptide in plasma at 120 min (vs. controls p<0.05) in agreement to the changes seen by measuring the totality of the TLQP peptides. In 20 pancreas sections we found the presence of the C3a-R1, involved in insulin secretion, and previously identified as a TLQP-21 receptor. Hence, after a glucose load, TLQP-21, may 2 be released by the pancreas into the plasma, returning to the pancreas in order to modulate the insulin secretion through the C3a-R1. Keywords: TLQP-21, glucose, insulin, VGF, metabolism 5 Short title: TLQP-21 and glucose load S3 Fig. RP-HPLC of plasma coupled to ELISA. Elution profile of TLQP-62 standard peptide (retention time 22-25 min) (a), samples in normal conditions (b) after 30 min (c) and after 120 min (d) of glucose load with evidenced the elution interval of fractions reactive with TLQP-antiserum by ELISA (e). The increase of 5 TLQP-62 at 30 and 120 min is not statistically significant (e: 30, 120 min vs. controls p>0.05). Pmol/ug prot.TOT: picomoles/micrograms of total proteins; mAU: milliabsorbance unit. ACKNOWLEDGMENTS This work was supported by grants of the University of Cagliari (FIR, Cocco), Professors 10 J.M. Polak and S.R. Bloom are thanked for antibodies. Declaration of interest:there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease

Gedam,

Zheng

2024

Eur J Immunol

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. Despite its widespread prevalence, our comprehension of the intricate mechanisms governing the pathogenesis of the disease remains incomplete, posing a challenge for the development of efficient therapies. Pathologically characterized by the presence of amyloid β plaques and neurofibrillary tau tangles, AD is also accompanied by the hyperactivation of glial cells and the immune system. The complement cascade, the evolutionarily conserved innate immune pathway, has emerged as a significant contributor to AD. This review focuses on one of the complement components, the C3a receptor (C3aR), covering its structure, ligand‐receptor interaction, intracellular signaling and its functional consequences. Drawing insights from cellular and AD mouse model studies, we present the multifaceted role of complement C3aR signaling in AD and attempt to convey to the readers that C3aR acts as a crucial immune and metabolic modulator to influence AD pathogenesis. Building on this framework, the objective of this review is to inform future research endeavors and facilitate the development of therapeutic strategies for this challenging condition.

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Complement 3a receptor in dorsal horn microglia mediates pronociceptive neuropeptide signaling

Cited by 32 publications

References 55 publications

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

Changes of TLQP-21 in Response to Glucose Load

Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease

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