Skip to main content

Advertisement

SpringerLink
Log in

Regulation of Macrophage Biology by Lithium: A New Look at an Old Drug

  • PERSPECTIVE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Lithium (Li) continues to be a standard small compound used for the treatment of neurological disorders. Besides neuronal cells, Li is also known to affect immune cell function. In spite of its clinical use, potential mechanisms by which Li modulates immune cells, especially macrophages and its clinical relevance in bipolar patients are not well understood. Here, we provide an overview of the literature with regard to Li’s effects on monocytes and macrophages. We have also included some of our results showing that Li differentially modulates chemokine gene expression in the absence and presence of Toll-like receptor-4 stimulation in a human macrophage model. Given that Li has a wide range of intracellular targets both in macrophages as well as in other cell types, more studies are needed to further understand the mechanistic basis of Li’s effect in neurological and other inflammatory diseases. These studies could undoubtedly identify new therapeutic targets for treating such diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Anur P, Yates J, Garbati MR, Vanderwerf S, Keeble W, Rathbun K, Hays LE, Tyner JW, Svahn J, Cappelli E, Dufour C, Bagby GC (2012) p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes. Blood 119:1992–2002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Arena A, Capozza AB, Orlando ME, Curro F, Losi E, Chillemi S, Mesiti M, Merendino RA (1997) In vitro effects of lithium chloride on TNF alpha and IL-6 production by monocytes from breast cancer patients. J Chemother (Florence, Italy) 9:219–226

    Article  CAS  Google Scholar 

  • Balon R, Berchou R (1986) Hematologic side effects of psychotropic drugs. Psychosomatics 27:119–120,125–117

    Google Scholar 

  • Beurel E, Jope RS (2008) Differential regulation of STAT family members by glycogen synthase kinase-3. J Biol Chem 283:21934–21944

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Beyaert R, Schulze-Osthoff K, Van Roy F, Fiers W (1991) Lithium chloride potentiates tumor necrosis factor-induced and interleukin 1-induced cytokine and cytokine receptor expression. Cytokine 3:284–291

    Article  CAS  PubMed  Google Scholar 

  • Beyaert R, Schulze-Osthoff K, Van Roy F, Fiers W (1992) Synergistic induction of interleukin-6 by tumor necrosis factor and lithium chloride in mice: possible role in the triggering and exacerbation of psoriasis by lithium treatment. Eur J Immunol 22:2181–2184

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Wu Y, Zhu M, Deng Q, Nie X, Li M, Wu M, Huang X (2013) Lithium chloride promotes host resistance against Pseudomonas aeruginosa keratitis. Mol Vision 19:1502–1514

    CAS  Google Scholar 

  • Chiu CT, Chuang DM (2010) Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther 128:281–304

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Choi SE, Jang HJ, Kang Y, Jung JG, Han SJ, Kim HJ, Kim DJ, Lee KW (2010) Atherosclerosis induced by a high-fat diet is alleviated by lithium chloride via reduction of VCAM expression in ApoE-deficient mice. Vasc Pharmacol 53:264–272

    Article  CAS  Google Scholar 

  • Conductier G, Blondeau N, Guyon A, Nahon JL, Rovere C (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 224(1–2):93–100

    Google Scholar 

  • Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • De Meyer I, Martinet W, Van Hove CE, Schrijvers DM, Hoymans VY, Van Vaeck L, Fransen P, Bult H, De Meyer GR (2011) Inhibition of inositol monophosphatase by lithium chloride induces selective macrophage apoptosis in atherosclerotic plaques. Br J Pharmacol 162:1410–1423

    Article  PubMed Central  PubMed  Google Scholar 

  • De Sarno P, Axtell RC, Raman C, Roth KA, Alessi DR, Jope RS (2008) Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. J Immunol 181:338–345

    Article  PubMed Central  PubMed  Google Scholar 

  • Gualtieri RJ, Berne RM, McGrath HE, Huster WJ, Quesenberry PJ (1986) Effect of adenine nucleotides on granulopoiesis and lithium-induced granulocytosis in long-term bone marrow cultures. Exp Hematol 14:689–695

    CAS  PubMed  Google Scholar 

  • Hart DA, Done SJ, Benediktsson H, Lenz SP (1994) Partial characterization of the enhanced survival of female NZB/W mice treated with lithium chloride. Int J Immunopharmacol 16:825–833

    Article  CAS  PubMed  Google Scholar 

  • Hui W, Litherland GJ, Jefferson M, Barter MJ, Elias MS, Cawston TE, Rowan AD, Young DA (2010) Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway. Rheumatology 49:2043–2053

    Article  CAS  PubMed  Google Scholar 

  • Hull M, Lee E, Lee T, Anand N, Lalone V, Parameswaran N (2013) Lithium chloride induces TNFalpha in mouse macrophages via MEK-ERK-dependent pathway. J Cell Biochem 115(1):71–80

    Google Scholar 

  • Irwin R, Lee T, Young VB, Parameswaran N, McCabe LR (2013) Colitis-induced bone loss is gender dependent and associated with increased inflammation. Inflamm Bowel Dis 19:1586–1597

    PubMed  Google Scholar 

  • Kleinerman ES, Knowles RD, Blick MB, Zwelling LA (1989) Lithium chloride stimulates human monocytes to secrete tumor necrosis factor/cachectin. J Leukoc Biol 46:484–492

    CAS  PubMed  Google Scholar 

  • Knijff EM, Breunis MN, Kupka RW, de Wit HJ, Ruwhof C, Akkerhuis GW, Nolen WA, Drexhage HA (2007) An imbalance in the production of IL-1beta and IL-6 by monocytes of bipolar patients: restoration by lithium treatment. Bipolar Disord 9:743–753

    Article  CAS  PubMed  Google Scholar 

  • Kucharz EJ, Sierakowski SJ, Goodwin JS (1993) Lithium in vitro enhances interleukin-2 production by T cells from patients with systemic lupus erythematosus. Immunopharmacol Immunotoxicol 15:515–523

    Article  CAS  PubMed  Google Scholar 

  • Lee T, Lee E, Irwin R, Lucas PC, McCabe LR, Parameswaran N (2013) beta-Arrestin-1 deficiency protects mice from experimental colitis. Am J Pathol 182:1114–1123

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leemasawatdigul K, Gappa-Fahlenkamp H (2011) Effect of storage conditions on the stability of recombinant human MCP-1/CCL2. Biol J Int Assoc Biol Stand 39:29–32

    CAS  Google Scholar 

  • Lehto SM, Niskanen L, Herzig KH, Tolmunen T, Huotari A, Viinamaki H, Koivumaa-Honkanen H, Honkalampi K, Ruotsalainen H, Hintikka J (2010) Serum chemokine levels in major depressive disorder. Psychoneuroendocrinology 35:226–232

    Article  CAS  PubMed  Google Scholar 

  • Leonard BE (2007) Inflammation, depression and dementia: are they connected? Neurochem Res 32:1749–1756

    Article  CAS  PubMed  Google Scholar 

  • Liu KJ, Lee YL, Yang YY, Shih NY, Ho CC, Wu YC, Huang TS, Huang MC, Liu HC, Shen WW, Leu SJ (2011) Modulation of the development of human monocyte-derived dendritic cells by lithium chloride. J Cell Physiol 226:424–433

    Article  CAS  PubMed  Google Scholar 

  • Maes M, Song C, Lin AH, Pioli R, Kenis G, Kubera M, Bosmans E (1999) In vitro immunoregulatory effects of lithium in healthy volunteers. Psychopharmacology 143:401–407

    Article  CAS  PubMed  Google Scholar 

  • Merendino RA, Arena A, Gangemi S, Ruello A, Losi E, Bene A, D’Ambrosio FP (2000a) In vitro interleukin-8 production by monocytes treated with lithium chloride from breast cancer patients. Tumori 86:149–152

    CAS  Google Scholar 

  • Merendino RA, Arena A, Gangemi S, Ruello A, Losi E, Bene A, Valenti A, D’Ambrosio FP (2000b) In vitro effect of lithium chloride on interleukin-15 production by monocytes from IL-breast cancer patients. J Chemother (Florence, Italy) 12:252–257

    Article  CAS  Google Scholar 

  • Moresco EM, LaVine D, Beutler B (2011) Toll-like receptors. Curr Biol CB 21:R488–R493

    Article  CAS  Google Scholar 

  • Murphy DL, Goodwin FK, Bunney WE Jr (1971) Leukocytosis during lithium treatment. Am J Psychiatry 127:1559–1561

    CAS  PubMed  Google Scholar 

  • Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nahman S, Belmaker RH, Azab AN (2012) Effects of lithium on lipopolysaccharide-induced inflammation in rat primary glia cells. Innate Immun 18:447–458

    Article  CAS  PubMed  Google Scholar 

  • Packiriswamy N, Lee T, Raghavendra PB, Durairaj H, Wang H, Parameswaran N (2013) G-protein-coupled receptor kinase-5 mediates inflammation but does not regulate cellular infiltration or bacterial load in a polymicrobial sepsis model in mice. J Innate Immun 5:401–413

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patial S, Shahi S, Saini Y, Lee T, Packiriswamy N, Appledorn DM, Lapres JJ, Amalfitano A, Parameswaran N (2011a) G-protein coupled receptor kinase 5 mediates lipopolysaccharide-induced NFkappaB activation in primary macrophages and modulates inflammation in vivo in mice. J Cell Physiol 226:1323–1333

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patial S, Saini Y, Parvataneni S, Appledorn DM, Dorn GW 2nd, Lapres JJ, Amalfitano A, Senagore P, Parameswaran N (2011b) Myeloid-specific GPCR kinase-2 negatively regulates NF-kappaB1p105-ERK pathway and limits endotoxemic shock in mice. J Cell Physiol 226:627–637

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roskoski R Jr (2012) ERK1/2 MAP kinases: structure, function, and regulation. Pharm Res Off J Italian Pharmacol Soc 66:105–143

    Article  CAS  Google Scholar 

  • Savarin-Vuaillat C, Ransohoff RM (2007) Chemokines and chemokine receptors in neurological disease: raise, retain, or reduce? Neurother J Am Soc Exp NeuroTher 4:590–601

    Article  CAS  Google Scholar 

  • Sharma D, Malik A, Lee E, Britton RA, Parameswaran N (2013) Gene dosage-dependent negative regulatory role of beta-arrestin-2 in polymicrobial infection-induced inflammation. Infect Immun 81:3035–3044

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shenkman L, Borkowsky W, Shopsin B (1980) Lithium as an immunologic adjuvant. Med Hypotheses 6:1–6

    Article  CAS  PubMed  Google Scholar 

  • Shenkman L, Borkowsky W, Holzman RS, Shopsin B (1978) Enhancement of lymphocyte and macrophage function in vitro by lithium chloride. Clin Immunol Immunopathol 10:187–192

    Article  CAS  PubMed  Google Scholar 

  • Shopsin B, Friedmann R, Gershon S (1971) Lithium and leukocytosis. Clin Pharmacol Ther 12:923–928

    CAS  PubMed  Google Scholar 

  • Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Investig 122:787–795

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tang A, Sharma A, Jen R, Hirschfeld AF, Chilvers MA, Lavoie PM, Turvey SE (2012) Inflammasome-mediated IL-1beta production in humans with cystic fibrosis. PloS One 7:e37689

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tisman G, Herbert V, Rosenblatt S (1973) Evidence that lithium induces human granulocyte proliferation: elevated serum vitamin B 12 binding capacity in vivo and granulocyte colony proliferation in vitro. Br J Haematol 24:767–771

    Article  CAS  PubMed  Google Scholar 

  • Tsuji S, Morinobu S, Tanaka K, Kawano K, Yamawaki S (2003) Lithium, but not valproate, induces the serine/threonine phosphatase activity of protein phosphatase 2A in the rat brain, without affecting its expression. J Neural Transm 110:413–425

    Article  CAS  PubMed  Google Scholar 

  • Vuletic S, Dong W, Wolfbauer G, Tang C, Albers JJ (2011) PLTP regulates STAT3 and NFkappaB in differentiated THP1 cells and human monocyte-derived macrophages. Biochim Biophys Acta 1813:1917–1924

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Waisberg M, Cerqueira GC, Yager SB, Francischetti IM, Lu J, Gera N, Srinivasan P, Miura K, Rada B, Lukszo J, Barbian KD, Leto TL, Porcella SF, Narum DL, El-Sayed N, Miller LH, Pierce SK (2012) Plasmodium falciparum merozoite surface protein 1 blocks the proinflammatory protein S100P. Proc Natl Acad Sci U S A 109:5429–5434

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang L, Zhang L, Zhao X, Zhang M, Zhao W, Gao C (2013) Lithium Attenuates IFN-beta Production and Antiviral Response via Inhibition of TANK-Binding Kinase 1 Kinase Activity. J Immunol. 191(8):4392–4398

    Google Scholar 

  • Wang Y, Huang WC, Wang CY, Tsai CC, Chen CL, Chang YT, Kai JI, Lin CF (2009) Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis. Br J Pharmacol 157:1004–1013

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Watanabe S, Taguchi K, Nakashima Y, Ebara T, Iguchi K (1974) Leukocytosis during lithium treatment and its correlation to serum lithium level. Folia Psychiatr Neurol Jpn 28:161–165

    CAS  PubMed  Google Scholar 

  • Zhang M, Jin W, Zhou X, Yu J, Lee AJ, Sun SC (2009) Deregulation of Tpl2 and NF-kappaB signaling and induction of macrophage apoptosis by the anti-depressant drug lithium. Cell Signal 21:559–566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhen X, Torres C, Friedman E (2002) Lithium regulates protein tyrosine phosphatase activity in vitro and in vivo. Psychopharmacology 162:379–384

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the support from NIH (grants HL095637, AR055726 and AR056680 to N.P.).

Conflict of Interest

Authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Physiology and Division of Human Pathology, Michigan State University, 2201 Biomedical Physical Sciences building, East Lansing, MI, 48823, USA

    Pongali B. Raghavendra, Eunhee Lee & Narayanan Parameswaran

Authors
  1. Pongali B. Raghavendra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eunhee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Narayanan Parameswaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Narayanan Parameswaran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Raghavendra, P.B., Lee, E. & Parameswaran, N. Regulation of Macrophage Biology by Lithium: A New Look at an Old Drug. J Neuroimmune Pharmacol 9, 277–284 (2014). https://doi.org/10.1007/s11481-013-9516-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-013-9516-y

Keywords

Search

Navigation