Neuroinflammation is a key feature shared by most, if not all, neuropathologies. It involves complex biological processes that act as a protective mechanism to fight against the injurious stimuli, but it can lead to tissue damage if self-perpetuating. In this context, microglia, the main cellular actor of neuroinflammation in the brain, are seen as a double-edged sword. By phagocyting neuronal debris, these cells can not only provide tissue repair but can also contribute to neuronal damage by releasing harmful substances, including inflammatory cytokines. The mechanisms guiding these apparent opposing actions are poorly known. The endocannabinoid system modulates the release of inflammatory factors such as cytokines and could represent a functional link between microglia and neuroinflammatory processes. According to transcriptomic databases and in vitro studies, microglia, the main source of cytokines in pathological conditions, express the cannabinoid type 1 receptor (CB1R).
Methods:
We thus developed a conditional mouse model of CB1R deletion specifically in microglia, which was subjected to an immune challenge (peripheral lipopolysaccharide injection).
Results:
Our results reveal that microglial CB1R differentially controls sickness behavior in males and females.
Conclusion:
These findings add to the comprehension of neuroinflammatory processes and might be of great interest for future studies aimed at developing therapeutic strategies for brain disorders with higher prevalence in men.
Get full access to this article
View all access options for this article.
References
1.
SochockaM, DinizBS, LeszekJ. Inflammatory response in the CNS: friend or foe?. Mol Neurobiol. 2017; 54:8071–8089.
2.
RansohoffRM, BrownMA. Innate immunity in the central nervous system. J Clin Invest. 2012; 122:1164–1171.
3.
NimmerjahnA, KirchhoffF, HelmchenF. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005; 308:1314–1318.
4.
FärberK, KettenmannH. Physiology of microglial cells. Brain Res Brain Res Rev. 2005; 48:133–143.
5.
DantzerR, O'ConnorJC, FreundGG, et al.From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008; 9:46–56.
6.
NadjarA, BluthéR-M, MayMJ, et al.Inactivation of the cerebral NFkappaB pathway inhibits interleukin-1beta-induced sickness behavior and c-Fos expression in various brain nuclei. Neuropsychopharmacology. 2005; 30:1492–1499.
7.
YirmiyaR, GoshenI. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011; 25:181–213.
8.
CorreaF, MestreL, Molina-HolgadoE, et al.The role of cannabinoid system on immune modulation: therapeutic implications on CNS inflammation. Mini Rev Med Chem. 2005; 5:671–675.
9.
Di MarzoV. Targeting the endocannabinoid system: to enhance or reduce?. Nat Rev Drug Discov. 2008; 7:438–455.
10.
StellaN. Endocannabinoid signaling in microglial cells. Neuropharmacology. 2009; 56(Suppl 1):244–253.
11.
LisboaSF, GomesFV, TerzianALB, et al.The endocannabinoid system and anxiety. Vitam Horm. 2017; 103:193–279.
12.
Di MarzoV. Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight. Nat Neurosci. 2011; 14:9–15.
13.
LutzB, MarsicanoG, MaldonadoR, et al.The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci. 2015; 16:705–718.
14.
ParsonsLH, HurdYL. Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci. 2015; 16:579–594.
15.
NúñezE, BenitoC, PazosMR, et al.Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004; 53:208–213.
MechaM, Carrillo-SalinasFJ, FeliúA, et al.Microglia activation states and cannabinoid system: therapeutic implications. Pharmacol Ther. 2016; 166:40–55.
18.
GuidaF, LuongoL, BoccellaS, et al.Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. Sci Rep. 2017; 7:375.
19.
GaliègueS, MaryS, MarchandJ, et al.Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995; 232:54–61.
20.
EstradaJA, ContrerasI. Endocannabinoid receptors in the CNS: potential drug targets for the prevention and treatment of neurologic and psychiatric disorders. Curr Neuropharmacol. 2020; 18:769–787.
21.
Galán-GangaM, Del RíoR, Jiménez-MorenoN, et al.Cannabinoid CB2 receptor modulation by the transcription factor NRF2 is specific in microglial cells. Cell Mol Neurobiol. 2020; 40:167–177.
22.
TanakaM, SackettS, ZhangY. Endocannabinoid modulation of microglial phenotypes in neuropathology. Front Neurol. 2020; 11:87.
23.
CabralGA, Marciano-CabralF. Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol. 2005; 78:1192–1197.
24.
DuncanM, GalicMA, WangA, et al.Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation. Am J Physiol Regul Integr Comp Physiol. 2013; 305:R224–R231.
25.
MechaM, FeliúA, Carrillo-SalinasFJ, et al.Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behav Immun. 2015; 49:233–245.
26.
NavarroG, Borroto-EscuelaD, AngelatsE, et al.Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia. Brain Behav Immun. 2018; 67:139–151.
27.
SteinerAA, MolchanovaAY, DoganMD, et al.The hypothermic response to bacterial lipopolysaccharide critically depends on brain CB1, but not CB2 or TRPV1, receptors. J Physiol (Lond). 2011; 589:2415–2431.
28.
GoldmannT, WieghoferP, MüllerPF, et al.A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci. 2013; 16:1618–1626.
29.
ParkhurstCN, YangG, NinanI, et al.Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013; 155:1596–1609.
30.
ThionMS, LowD, SilvinA, et al.Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell. 2018; 172:500.e16–516.e16.
31.
KleinSL, FlanaganKL. Sex differences in immune responses. Nat Rev Immunol. 2016; 16:626–638.
32.
LasselinJ, LekanderM, AxelssonJ, et al.Sex differences in how inflammation affects behavior: what we can learn from experimental inflammatory models in humans. Front Neuroendocrinol. 2018; 50:91–106.
33.
HanJ, KesnerP, Metna-LaurentM, et al.Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. 2012; 148:1039–1050.
34.
YonaS, KimK-W, WolfY, et al.Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013; 38:79–91.
35.
MarsicanoG, GoodenoughS, MonoryK, et al.CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003; 302:84–88.
36.
CazarethJ, GuyonA, HeurteauxC, et al.Molecular and cellular neuroinflammatory status of mouse brain after systemic lipopolysaccharide challenge: importance of CCR2/CCL2 signaling. J Neuroinflammation. 2014; 11:132.
37.
FuHQ, YangT, XiaoW, et al.Prolonged neuroinflammation after lipopolysaccharide exposure in aged rats. PLoS One. 2014; 9:e106331.
38.
IpJPK, NoçonAL, HoferMJ, et al.Lipocalin 2 in the central nervous system host response to systemic lipopolysaccharide administration. J Neuroinflammation. 2011; 8:124.
39.
SaraivaC, Barata-AntunesS, SantosT, et al.Histamine modulates hippocampal inflammation and neurogenesis in adult mice. Sci Rep. 2019; 9:8384.
40.
TaoX, YanM, WangL, et al.Homeostasis imbalance of microglia and astrocytes leads to alteration in the metabolites of the kynurenine pathway in LPS-induced depressive-like mice. Int J Mol Sci. 2020; 21:1460.
41.
LayéS, GheusiG, CremonaS, et al.Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression. Am J Physiol Regul Integr Comp Physiol. 2000; 279:R93–R98.
42.
MadoreC, JoffreC, DelpechJC, et al.Early morphofunctional plasticity of microglia in response to acute lipopolysaccharide. Brain Behav Immun. 2013; 34:151–158.
43.
MingamR, De SmedtV, AmédéeT, et al.In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain. Brain Behav Immun. 2008; 22:234–244.
MadoreC, LeyrolleQ, MorelL, et al.Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain. Nat Commun. 2020; 11:6133.
46.
Bosch-BoujuC, LarrieuT, LindersL, et al.Endocannabinoid-mediated plasticity in nucleus accumbens controls vulnerability to anxiety after social defeat stress. Cell Rep. 2016; 16:1237–1242.
47.
DinelA-L, AndréC, AubertA, et al.Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome. PLoS One. 2011; 6:e24325.
48.
MoranisA, DelpechJ-C, De Smedt-PeyrusseV, et al.Long term adequate N-3 polyunsaturated fatty acid diet protects from depressive-like behavior but not from working memory disruption and brain cytokine expression in aged mice. Brain Behav Immun. 2012; 26:721–731.
49.
LabrousseVF, NadjarA, JoffreC, et al.Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice. PLoS One. 2012; 7:e36861.
50.
DelpechJ-C, ThomazeauA, MadoreC, et al.Dietary N-3 PUFAs deficiency increases vulnerability to inflammation-induced spatial memory impairment. Neuropsychopharmacology. 2015; 40:2774–2787.
51.
LabrousseVF, LeyrolleQ, AmadieuC, et al.Dietary omega-3 deficiency exacerbates inflammation and reveals spatial memory deficits in mice exposed to lipopolysaccharide during gestation. Brain Behav Immun. 2018; 73:427–440.
52.
MadoreC, NadjarA, DelpechJ-C, et al.Nutritional N-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes. Brain Behav Immun. 2014; 41:22–31.
53.
FurubeE, KawaiS, InagakiH, et al.Brain region-dependent heterogeneity and dose-dependent difference in transient microglia population increase during lipopolysaccharide-induced inflammation. Sci Rep. 2018; 8:2203.
54.
NahirneyPC, TremblayM-E. Brain ultrastructure: putting the pieces together. Front Cell Dev Biol. 2021; 9:629503.
55.
AlperinaE, IdovaG, ZhukovaE, et al.Cytokine variations within brain structures in rats selected for differences in aggression. Neurosci Lett. 2019; 692:193–198.
56.
SkellyDT, HennessyE, DansereauM-A, et al.A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1B, TNF-α and IL-6 challenges in C57BL/6 mice. PLoS One. 2013; 8:e69123.
57.
TeelingJL, CunninghamC, NewmanTA, et al.The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: implications for a role of COX-1. Brain Behav Immun. 2010; 24:409–419.
58.
ChomczynskiP, SacchiN. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987; 162:156–159.
59.
BustinSA, BenesV, GarsonJA, et al.The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009; 55:611–622.
60.
XieF, XiaoP, ChenD, et al.MiRDeepFinder: a MiRNA analysis tool for deep sequencing of plant small RNAs. Plant Mol Biol. 2012; 80:75–84.
61.
BellocchioL, Soria-GómezE, QuartaC, et al.Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB1₁ receptor blockade. Proc Natl Acad Sci U S A. 2013; 110:4786–4791.
62.
Busquets-GarciaA, BainsJ, MarsicanoG. CB1 receptor signaling in the brain: extracting specificity from ubiquity. Neuropsychopharmacology. 2018; 43:4–20.
63.
DubreucqS, DurandA, MatiasI, et al.Ventral tegmental area cannabinoid type-1 receptors control voluntary exercise performance. Biol Psychiatry. 2013; 73:895–903.
64.
HaoS, AvrahamY, MechoulamR, et al.Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur J Pharmacol. 2000; 392:147–156.
65.
ReyAA, PurrioM, ViverosM-P, et al.Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology. 2012; 37:2624–2634.
66.
Gutiérrez-RodríguezA, Bonilla-Del RíoI, PuenteN, et al.Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. Glia. 2018; 66:1417–1431.
67.
Jimenez-BlascoD, Busquets-GarciaA, Hebert-ChatelainE, et al.Glucose metabolism links astroglial mitochondria to cannabinoid effects. Nature. 2020; 583:603–608.
68.
DiPatrizioNV, PiomelliD. The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends Neurosci. 2012; 35:403–411.
69.
LayéS, NadjarA, JoffreC, et al.Anti-inflammatory effects of omega-3 fatty acids in the brain: physiological mechanisms and relevance to pharmacology. Pharmacol Rev. 2018; 70:12–38.
70.
MazierW, SaucisseN, Gatta-CherifiB, et al.The endocannabinoid system: pivotal orchestrator of obesity and metabolic disease. Trends Endocrinol Metab. 2015; 26:524–537.
71.
PrinzM, JungS, PrillerJ. Microglia biology: one century of evolving concepts. Cell. 2019; 179:292–311.
DantzerR. Cytokine-induced sickness behavior: where do we stand?. Brain Behav Immun. 2001; 15:7–24.
74.
SchwartzMW, WoodsSC, PorteD, et al.Central nervous system control of food intake. Nature. 2000; 404:661–671.
75.
GoodDW, GeorgeT, WattsBA. Toll-like receptor 2 is required for LPS-induced toll-like receptor 4 signaling and inhibition of ion transport in renal thick ascending limb. J Biol Chem. 2012; 287:20208–20220.
76.
ZhangY, ChenK, SloanSA, et al.An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34:11929–11947.
77.
GritonM, KonsmanJP. Neural pathways involved in infection-induced inflammation: recent insights and clinical implications. Clin Auton Res. 2018; 28:289–299.
78.
KonsmanJP, DantzerR. How the immune and nervous systems interact during disease-associated anorexia. Nutrition. 2001; 17:664–668.
79.
MaggiL, ScianniM, BranchiI, et al.CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci. 2011; 5:22.
80.
MiliorG, LecoursC, SamsonL, et al.Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress. Brain Behav Immun. 2016; 55:114–125.
81.
RogersJT, MorgantiJM, BachstetterAD, et al.CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci. 2011; 31:16241–16250.
82.
ErblichB, ZhuL, EtgenAM, et al.Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One. 2011; 6:e26317.
83.
GinhouxF, GreterM, LeboeufM, et al.Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010; 330:841–845.
84.
ElmoreMRP, NajafiAR, KoikeMA, 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.
85.
HaoS, DeyA, YuX, et al.Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain Behav Immun. 2016; 51:230–239.
86.
BellocchioL, LafenêtreP, CannichA, et al.Bimodal control of stimulated food intake by the endocannabinoid system. Nat Neurosci. 2010; 13:281–283.
87.
LafenêtreP, ChaouloffF, MarsicanoG. Bidirectional regulation of novelty-induced behavioral inhibition by the endocannabinoid system. Neuropharmacology. 2009; 57:715–721.
88.
Metna-LaurentM, Soria-GómezE, VerrierD, et al.Bimodal control of fear-coping strategies by CB1₁ cannabinoid receptors. J Neurosci. 2012; 32:7109–7118.
89.
Lopez-RodriguezAB, SiopiE, FinnDP, et al.CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice. Cereb Cortex. 2015; 25:35–45.
90.
SuárezJ, RiveraP, Aparisi ReyA, et al.Adipocyte cannabinoid CB1 receptor deficiency alleviates high fat diet-induced memory deficit, depressive-like behavior, neuroinflammation and impairment in adult neurogenesis. Psychoneuroendocrinology. 2019; 110:104418.
91.
KentS, Bret-DibatJL, KelleyKW, et al.Mechanisms of sickness-induced decreases in food-motivated behavior. Neurosci Biobehav Rev. 1996; 20:171–175.
92.
DantzerR, KelleyKW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007; 21:153–160.
93.
WaldburgerJ-M, FiresteinGS. Regulation of peripheral inflammation by the central nervous system. Curr Rheumatol Rep. 2010; 12:370–378.
94.
CaiKC, van MilS, MurrayE, et al.Age and sex differences in immune response following LPS treatment in mice. Brain Behav Immun. 2016; 58:327–337.
95.
RossettiAC, PaladiniMS, TrepciA, et al.Differential neuroinflammatory response in male and female mice: a role for BDNF. Front Mol Neurosci. 2019; 12:166.
96.
MouihateA, ChenX, PittmanQJ. Interleukin-1beta fever in rats: gender difference and estrous cycle influence. Am J Physiol. 1998; 275:R1450–R1454.
97.
SchneidersJ, FuchsF, DammJ, et al.The transcription factor nuclear factor interleukin 6 mediates pro- and anti-inflammatory responses during LPS-induced systemic inflammation in mice. Brain Behav Immun. 2015; 48:147–164.
98.
GrabertK, MichoelT, KaravolosMH, et al.Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci. 2016; 19:504–516.
99.
HammondTR, DufortC, Dissing-OlesenL, et al.Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity. 2019; 50:253.e6–271.e6.
100.
Keren-ShaulH, SpinradA, WeinerA, et al.A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017; 169:1276.e17–1290.e17.
101.
MasudaT, SankowskiR, StaszewskiO, et al.Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature. 2019; 566:388–392.
102.
FarhangB, DiazS, TangSL, et al.Sex differences in the cannabinoid regulation of energy homeostasis. Psychoneuroendocrinology. 2009; 34(Suppl 1):S237–S246.
103.
LaurikainenH, TuominenL, TikkaM, et al.; Sex difference in brain CB1 receptor availability in man. Neuroimage. 2019; 184:834–842.
104.
CastelliMP, FaddaP, CasuA, et al.Male and female rats differ in brain cannabinoid CB1 receptor density and function and in behavioural traits predisposing to drug addiction: effect of ovarian hormones. Curr Pharm Des. 2014; 20:2100–2113.
105.
TayTL, CarrierM, TremblayM-È. Physiology of microglia. Adv Exp Med Biol. 2019; 1175:129–148.
106.
LenzKM, NugentBM, HaliyurR, et al.Microglia are essential to masculinization of brain and behavior. J Neurosci. 2013; 33:2761–2772.
107.
MoutonPR, LongJM, LeiD-L, et al.Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res. 2002; 956:30–35.
108.
NelsonLH, WardenS, LenzKM. Sex differences in microglial phagocytosis in the neonatal hippocampus. Brain Behav Immun. 2017; 64:11–22.
109.
SchwarzJM, SholarPW, BilboSD. Sex differences in microglial colonization of the developing rat brain. J Neurochem. 2012; 120:948–963.
110.
SorgeRE, MapplebeckJCS, RosenS, et al.Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015; 18:1081–1083.
111.
BollingerJL, Bergeon BurnsCM, WellmanCL. Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain Behav Immun. 2016; 52:88–97.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
