Background: Traumatic spinal cord injury (SCI) induces a robust local inflammatory response that can both facilitate repair and exacerbate pathology. Hydroxycarboxylic acid receptor 2 (Hcar2) is known to exert immunomodulatory effects; however, its role in SCI and its potential for targeting Hcar2 to alleviate motor deficits remain unclear.
Methods: The spinal cord transcriptome following SCI, with a focus on Hcar2, was analysed via publicly available single-cell RNA sequencing datasets from mice and rhesus macaques. Additionally, an in vivo SCI mouse model with Hcar2 knockout and an in vitro LPS-induced BV2 microglial model were established to assess Hcar2 gene and protein expression, microglial activation and inflammatory responses via bulk RNA sequencing, immunofluorescence staining, Western blotting, and real-time polymerase chain reaction. To evaluate the protective effects of Hcar2 activation, niacin, a known Hcar2 agonist, was administered to mice or BV2 cells, followed by assessments of the inflammatory response and motor function.
Results: Hcar2 gene expression, which was enriched predominantly in spinal cord microglia, was upregulated following SCl, peaking at 7 days post-SCl. Genetic knockout of Hcar2 decreased the percentage of impaired anti-inflammatory polarized microglia and increased the inflammatory response. In contrast, Hcar2 activation with niacin in LPS-stimulated microglia BV cell models reversed mitochondrial dysfunction, increased the oxygen consumption rate and reduced the expression of the cytokines IL-6 and IL-1β. The administration of niacin to SCl mice upregulated anti-inflammatory microglia, reduced the expression of multiple proinflammatory cytokines, increased the number of motor neurons and improved motor function recovery. Notably, all these protective effects were abolished by genetic loss of Hcar2.
Conclusions: Hcar2 serves as a critical regulator of microglial polarization, promoting the switch from a proinflammatory phenotype to an anti-inflammatory phenotype through immunometabolic reprogramming. Targeting Hcar2 with niacin may offer a translatable therapeutic strategy to improve functional recovery after SCl.
Key Points:
| [1] |
GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019; 18: 56-87.
|
| [2] |
Courtine G, Sofroniew MV. Spinal cord repair: advances in biology and technology. Nat Med. 2019; 25: 898-908.
|
| [3] |
Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nat Rev Dis Primers. 2017; 3:17018.
|
| [4] |
David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011; 12: 388-399.
|
| [5] |
Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol. 2011; 11: 775-787.
|
| [6] |
Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009; 29: 13435-13444.
|
| [7] |
Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol. 2016; 173: 649-665.
|
| [8] |
Gensel JC, Zhang B. Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. 2015; 1619: 1-11.
|
| [9] |
Graff EC, Fang H, Wanders D, Judd RL. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism. 2016; 65: 102-113.
|
| [10] |
Testai L, Guida F, Salerno S, et al. Hydroxyl carboxylic acid receptor-2 (HCAR2) as a potential target in neurometabolic diseases. Pharmacol Therapeut. 2025; 274:108909.
|
| [11] |
Tunaru S, Kero J, Schaub A, et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 2003; 9: 352-355.
|
| [12] |
Taing K, Chen L, Weng HR. Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain. Neural Regen Res. 2023; 18: 763-768.
|
| [13] |
Polito R, La Torre ME, Moscatelli F, et al. The ketogenic diet and neuroinflammation: the action of beta-hydroxybutyrate in a microglial cell line. Int J Mol Sci. 2023; 24(4): 3102.
|
| [14] |
He D, Fu S, Ye B, et al. Activation of HCA2 regulates microglial responses to alleviate neurodegeneration in LPS-induced in vivo and in vitro models. J Neuroinflammation. 2023; 20: 86.
|
| [15] |
Moutinho M, Puntambekar SS, Tsai AP, et al. The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer's disease. Sci Transl Med. 2022; 14(637):eabl7634.
|
| [16] |
Milich LM, Choi JS, Ryan C, et al. Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord. J Exp Med. 2021; 218(8):e20210040.
|
| [17] |
Fan Y, Wu X, Han S, et al. Single-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury. Nat Commun. 2023; 14: 4796.
|
| [18] |
Bellver-Landete V, Bretheau F, Mailhot B, et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun. 2019; 10: 518.
|
| [19] |
Brennan FH, Li Y, Wang C, et al. Microglia coordinate cellular interactions during spinal cord repair in mice. Nat Commun. 2022; 13: 4096.
|
| [20] |
Zha X, Zheng G, Skutella T, Kiening K, Unterberg A, Younsi A. Microglia: a promising therapeutic target in spinal cord injury. Neural Regen Res. 2025; 20: 454-463.
|
| [21] |
Mrdjen D, Pavlovic A, Hartmann FJ, et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity. 2018; 48: 380-395.e6.
|
| [22] |
Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014; 15: 300-312.
|
| [23] |
Galvan-Pena S, O'Neill LA. Metabolic reprograming in macrophage polarization. Front Immunol. 2014; 5: 420.
|
| [24] |
Elmore MR, Najafi AR, Koike MA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014; 82: 380-397.
|
| [25] |
Adams KL, Gallo V. The diversity and disparity of the glial scar. Nat Neurosci. 2018; 21: 9-15.
|
| [26] |
O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016; 16: 553-565.
|
| [27] |
Hu X, Leak RK, Shi Y, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol. 2015; 11: 56-64.
|
| [28] |
Tan W, Su P-YP, Leff J, et al. Distinct phases of adult microglia proliferation: a Myc-mediated early phase and a Tnfaip3-mediated late phase. Cell Disc. 2022; 8(1): 34.
|
| [29] |
Minhas PS, Latif-Hernandez A, McReynolds MR, et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature. 2021; 590: 122-128.
|
| [30] |
Bernier LP, York EM, MacVicar BA. Immunometabolism in the brain: how metabolism shapes microglial function. Trends Neurosci. 2020; 43: 854-869.
|
| [31] |
Huber E, David G, Thompson AJ, Weiskopf N, Mohammadi S, Freund P. Dorsal and ventral horn atrophy is associated with clinical outcome after spinal cord injury. Neurology. 2018; 90: e1510-e22.
|
| [32] |
Park J. Immunomodulatory strategies for spinal cord injury. Biomed J Sci Tech Res. 2022; 45: 36467-36470.
|
| [33] |
Lee CY, Chooi WH, Ng SY, Chew SY. Modulating neuroinflammation through molecular, cellular and biomaterial-based approaches to treat spinal cord injury. Bioeng Transl Med. 2023; 8:e10389.
|
| [34] |
Kelly B, O'Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015; 25: 771-784.
|
| [35] |
Cheng J, Zhang R, Xu Z, et al. Early glycolytic reprogramming controls microglial inflammatory activation. J Neuroinflammation. 2021; 18: 129.
|
| [36] |
Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G. Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab. 2009; 9: 265-276.
|
| [37] |
Offermanns S, Schwaninger M. Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation. Trends Mol Med. 2015; 21: 245-255.
|
| [38] |
Kostylina G, Simon D, Fey MF, Yousefi S, Simon HU. Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A). Cell Death Differ. 2008; 15: 134-142.
|
| [39] |
Li S, Zhao J, Song Z, et al. Niacin, an active form of vitamin B3, exerts antiviral function by recruiting β-arrestin through GPR109A to activate the phosphorylation of ERK and STAT1 axis. J Virol. 2025; 99:e0151925.
|
| [40] |
Rahman M, Muhammad S, Khan MA, et al. The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun. 2014; 5: 3944.
|
| [41] |
Gasperi V, Sibilano M, Savini I, Catani MV. Niacin in the central nervous system: an update of biological aspects and clinical applications. Int J Mol Sci. 2019; 20(4): 974.
|
| [42] |
Guha L, Kumar H. Drug repurposing for spinal cord injury: progress towards therapeutic intervention for primary factors and secondary complications. Pharmaceut Med. 2023; 37: 463-490.
|
| [43] |
Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM, Popovich PG. Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma. 2006; 23: 635-659.
|
| [44] |
Raineteau O, Schwab ME. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci. 2001; 2: 263-273.
|
| [45] |
Grumbles RM, Thomas CK. Motoneuron death after human spinal cord injury. J Neurotrauma. 2017; 34: 581-590.
|
| [46] |
Bouhy D, Ghasemlou N, Lively S, et al. Inhibition of the Ca(2)(+)-dependent K(+) channel, KCNN4/KCa3.1, improves tissue protection and locomotor recovery after spinal cord injury. J Neurosci. 2011; 31: 16298-16308.
|
| [47] |
Miles GB, Hartley R, Todd AJ, Brownstone RM. Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion. Proc Natl Acad Sci U S A. 2007; 104: 2448-2453.
|
| [48] |
Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019; 19: 477-489.
|
| [49] |
Fu SP, Wang JF, Xue WJ, et al. Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson's disease models are mediated by GPR109A-dependent mechanisms. J Neuroinflammation. 2015; 12: 9.
|
| [50] |
Sarkar S, Yang R, R M. Control of brain tumor growth by reactivating myeloid cells with niacin. Sci Transl Med. 2020; 12:eaay9924.
|
RIGHTS & PERMISSIONS
2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
PDF
(9485KB)
