Two macrophages, osteoclasts and microglia: from development to pleiotropy

Abstract

Tissue-resident macrophages are highly specialized to their tissue-specific microenvironments, activated by various inflammatory signals and modulated by genetic and environmental factors. Osteoclasts and microglia are distinct tissue-resident cells of the macrophage lineage in bone and brain that are responsible for pathological changes in osteoporosis and Alzheimer’s disease (AD), respectively. Osteoporosis is more frequently observed in individuals with AD compared to the prevalence in general population. Diagnosis of AD is often delayed until underlying pathophysiological changes progress and cause irreversible damages in structure and function of brain. As such earlier diagnosis and intervention of individuals at higher risk would be indispensable to modify clinical courses. Pleiotropy is the phenomenon that a genetic variant affects multiple traits and the genetic correlation between two traits could suggest a shared molecular mechanism. In this review, we discuss that the Pyk2-mediated actin polymerization pathway in osteoclasts and microglia in bone and brain, respectively, is the horizontal pleiotropic mediator of shared risk factors for osteoporosis and AD.

References

[1] Vaananen HK, Zhao H, Mulari M, Halleen JM. The cell biology of osteoclast function. J. Cell Sci., 2000, 113:377-381

[2] Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol. Med, 2005, 11:76-81

[3] Hayman AR et al. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development, 1996, 122:3151-3162

[4] Vu TH et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell, 1998, 93:411-422

[5] Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science, 1996, 273:1236-1238

[6] Frattini A et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat. Genet., 2000, 25:343-346

[7] Black DM, Rosen CJ. Clinical practice. Postmenopausal osteoporosis. N. Engl. J. Med, 2016, 374:254-262

[8] Orwoll E et al. Alendronate for the treatment of osteoporosis in men. N. Engl. J. Med, 2000, 343:604-610

[9] El-Sobky TA, Elsobky E, Sadek I, Elsayed SM, Khattab MF. A case of infantile osteopetrosis: The radioclinical features with literature update. Bone Rep., 2016, 4:11-16

[10] Orchard PJ et al. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood, 2015, 126:270-276

[11] Safaiyan S et al. Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci., 2016, 19:995-998

[12] Stevens B et al. The classical complement cascade mediates CNS synapse elimination. Cell, 2007, 131:1164-1178

[13] Eroglu C, Barres BA. Regulation of synaptic connectivity by glia. Nature, 2010, 468:223-231

[14] Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat. Med., 2017, 23:1018-1027

[15] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell, 2019, 179:312-339

[16] Querfurth HW, LaFerla FM. Alzheimer’s disease. N. Engl. J. Med., 2010, 362:329-344

[17] Puig KL, Combs CK. Expression and function of APP and its metabolites outside the central nervous system. Exp. Gerontol., 2013, 48:608-611

[18] Li S, Liu B, Zhang L, Rong L. Amyloid beta peptide is elevated in osteoporotic bone tissues and enhances osteoclast function. Bone, 2014, 61:164-175

[19] Bedner P et al. Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain, 2015, 138:1208-1222

[20] Verkhratsky A, Steardo L, Parpura V, Montana V. Translational potential of astrocytes in brain disorders. Prog. Neurobiol., 2016, 144:188-205

[21] Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci., 2016, 17:201-207

[22] Cuello AC. Early and late CNS inflammation in Alzheimer’s disease: two extremes of a continuum? Trends Pharmacol. Sci., 2017, 38:956-966

[23] Ulland TK, Colonna M. TREM2—a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol., 2018, 14:667-675

[24] Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat. Rev. Immunol., 2019, 19:626-642

[25] Bianchin MM, Martin KC, de Souza AC, de Oliveira MA, Rieder CR. Nasu-Hakola disease and primary microglial dysfunction. Nat. Rev. Neurol., 2010, 6:523

[26] Amouzougan A et al. High prevalence of dementia in women with osteoporosis. Jt. Bone Spine, 2017, 84:611-614

[27] Chang KH et al. Increased risk of dementia in patients with osteoporosis: a population-based retrospective cohort analysis. Age, 2014, 36:967-975

[28] Zhou R, Deng J, Zhang M, Zhou HD, Wang YJ. Association between bone mineral density and the risk of Alzheimer’s disease. J. Alzheimers Dis., 2011, 24:101-108

[29] Loskutova N, Honea RA, Vidoni ED, Brooks WM, Burns JM. Bone density and brain atrophy in early Alzheimer’s disease. J. Alzheimers Dis., 2009, 18:777-785

[30] Lavin Y, Mortha A, Rahman A, Merad M. Regulation of macrophage development and function in peripheral tissues. Nat. Rev. Immunol., 2015, 15:731-744

[31] Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013, 496:445-455

[32] Gentek R et al. Epidermal gammadelta T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult. J. Exp. Med., 2018, 215:2994-3005

[33] Yoder MC, Hiatt K, Mukherjee P. In vivo repopulating hematopoietic stem cells are present in the murine yolk sac at day 9.0 postcoitus. Proc. Natl Acad. Sci. USA, 1997, 94:6776-6780

[34] Cumano A, Godin I. Ontogeny of the hematopoietic system. Annu Rev. Immunol., 2007, 25:745-785

[35] Hammond TR, Robinton D, Stevens B. Microglia and the brain: complementary partners in development and disease. Annu. Rev. Cell Dev. Biol., 2018, 34:523-544

[36] Nayak D, Roth TL, McGavern DB. Microglia development and function. Annu Rev. Immunol., 2014, 32:367-402

[37] Jacome-Galarza CE et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature, 2019, 568:541-545

[38] Mizoguchi T et al. Identification of cell cycle-arrested quiescent osteoclast precursors in vivo. J. Cell Biol., 2009, 184:541-554

[39] Yahara Y et al. Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair. Nat. Cell Biol., 2020, 22:49-59

[40] Hettinger J et al. Origin of monocytes and macrophages in a committed progenitor. Nat. Immunol., 2013, 14:821-830

[41] Colonna M. TREMs in the immune system and beyond. Nat. Rev. Immunol., 2003, 3:445-453

[42] Lowell, C. A. Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk. Cold Spring Harb. Perspect. Biol. 3, a002352 (2011).

[43] Kleinberger G et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med., 2014, 6:243ra86

[44] Wunderlich P et al. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J. Biol. Chem., 2013, 288:33027-33036

[45] Bouchon A, Hernandez-Munain C, Cella M, Colonna M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med, 2001, 194:1111-1122

[46] Hamerman JA, Ni M, Killebrew JR, Chu CL, Lowell CA. The expanding roles of ITAM adapters FcRgamma and DAP12 in myeloid cells. Immunol. Rev., 2009, 232:42-58

[47] Ivashkiv LB. Cross-regulation of signaling by ITAM-associated receptors. Nat. Immunol., 2009, 10:340-347

[48] McVicar DW, Trinchieri G. CSF-1R, DAP12 and beta-catenin: a menage a trois. Nat. Immunol., 2009, 10:681-683

[49] Koga T et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature, 2004, 428:758-763

[50] Humphrey MB et al. TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function. J. Bone Min. Res, 2006, 21:237-245

[51] Paloneva J et al. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J. Exp. Med., 2003, 198:669-675

[52] Cella M et al. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J. Exp. Med, 2003, 198:645-651

[53] Otero K et al. TREM2 and beta-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis. J. Immunol., 2012, 188:2612-2621

[54] Sessa G et al. Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur. J. Neurosci., 2004, 20:2617-2628

[55] Schmid CD et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J. Neurochem., 2002, 83:1309-1320

[56] Hsieh CL et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J. Neurochem, 2009, 109:1144-1156

[57] Lue LF, Schmitz C, Walker DG. What happens to microglial TREM2 in Alzheimer’s disease: Immunoregulatory turned into immunopathogenic? Neuroscience, 2015, 302:138-150

[58] Wang Y et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell, 2015, 160:1061-1071

[59] Keren-Shaul H et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell, 2017, 169:1276-1290.e17

[60] Krasemann S et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity, 2017, 47:566-581.e9

[61] MacDonald KP et al. The colony-stimulating factor 1 receptor is expressed on dendritic cells during differentiation and regulates their expansion. J. Immunol., 2005, 175:1399-1405

[62] Nandi S et al. The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev. Biol., 2012, 367:100-113

[63] Coussens L et al. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature, 1986, 320:277-280

[64] Aoki N, Ito K, Ito M. Isolation and characterization of mouse high-glycine/tyrosine proteins. J. Biol. Chem., 1997, 272:30512-30518

[65] Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol., 2004, 14:628-638

[66] Abboud SL, Woodruff K, Liu C, Shen V, Ghosh-Choudhury N. Rescue of the osteopetrotic defect in op/op mice by osteoblast-specific targeting of soluble colony-stimulating factor-1. Endocrinology, 2002, 143:1942-1949

[67] Dai XM, Zong XH, Sylvestre V, Stanley ER. Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1. Blood, 2004, 103:1114-1123

[68] Wiktor-Jedrzejczak W et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl Acad. Sci. USA, 1990, 87:4828-4832

[69] Lee AW, States DJ. Both src-dependent and -independent mechanisms mediate phosphatidylinositol 3-kinase regulation of colony-stimulating factor 1-activated mitogen-activated protein kinases in myeloid progenitors. Mol. Cell Biol., 2000, 20:6779-6798

[70] Xiong Y et al. A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation. J. Biol. Chem., 2011, 286:952-960

[71] Long CL, Berry WL, Zhao Y, Sun XH, Humphrey MB. E proteins regulate osteoclast maturation and survival. J. Bone Min. Res., 2012, 27:2476-2489

[72] Zou W et al. Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J. Cell Biol., 2007, 176:877-888

[73] Stanley, E. R. & Chitu, V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb. Perspect. Biol. 6, a021857 (2014).

[74] Ginhoux F et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 2010, 330:841-845

[75] Wang Y et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol., 2012, 13:753-760

[76] Michaelson MD et al. CSF-1 deficiency in mice results in abnormal brain development. Development, 1996, 122:2661-2672

[77] Lin H et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science, 2008, 320:807-811

[78] Rademakers R et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet, 2011, 44:200-205

[79] Kana V et al. CSF-1 controls cerebellar microglia and is required for motor function and social interaction. J. Exp. Med, 2019, 216:2265-2281

[80] Mancuso R et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain, 2019, 142:3243-3264

[81] Oppermann M. Chemokine receptor CCR5: insights into structure, function, and regulation. Cell. Signal., 2004, 16:1201-1210

[82] Weiss-Haljiti C et al. Involvement of phosphoinositide 3-kinase gamma, Rac, and PAK signaling in chemokine-induced macrophage migration. J. Biol. Chem., 2004, 279:43273-43284

[83] Del Corno M et al. HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood, 2001, 98:2909-2916

[84] Prahalad S et al. Association of two functional polymorphisms in the CCR5 gene with juvenile rheumatoid arthritis. Genes Immun., 2006, 7:468-475

[85] Han JH et al. Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood, 2001, 97:3349-3353

[86] Oba Y et al. MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Exp. Hematol., 2005, 33:272-278

[87] Lee JW et al. The HIV co-receptor CCR5 regulates osteoclast function. Nat. Commun., 2017, 8

[88] Taiwo BO et al. Less bone loss with maraviroc—versus tenofovir-containing antiretroviral therapy in the AIDS Clinical Trials Group A5303 Study. Clin. Infect. Dis., 2015, 61:1179-1188

[89] He J et al. CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature, 1997, 385:645-649

[90] Spudich S, Gonzalez-Scarano F. HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harb. Perspect. Med., 2012, 2:a007120

[91] Zhou, M. et al. CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory. Elife 5, e20985 (2016).

[92] Joy MT et al. CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury. Cell, 2019, 176:1143-1157.e13

[93] Ndhlovu LC et al. Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND). J. Neurovirol, 2014, 20:571-582

[94] Cross AK, Woodroofe MN. Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro. Glia, 1999, 28:183-189

[95] Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT. Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am. J. Pathol., 1998, 153:31-37

[96] Lee SH, Hollingsworth R, Kwon HY, Lee N, Chung CY. beta-arrestin 2-dependent activation of ERK1/2 is required for ADP-induced paxillin phosphorylation at Ser(83) and microglia chemotaxis. Glia, 2012, 60:1366-1377

[97] Sasaki H et al. Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily. J. Biol. Chem., 1995, 270:21206-21219

[98] Lev S et al. Protein tyrosine kinase PYK2 involved in Ca²⁺-induced regulation of ion channel and MAP kinase functions. Nature, 1995, 376:737-745

[99] Faccio R, Novack DV, Zallone A, Ross FP, Teitelbaum SL. Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by beta3 integrin. J. Cell Biol., 2003, 162:499-509

[100] Turner CE. Paxillin. Int J. Biochem. Cell Biol., 1998, 30:955-959

[101] Okigaki M et al. Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc. Natl Acad. Sci. USA, 2003, 100:10740-10745

[102] Suarez C, Kovar DR. Internetwork competition for monomers governs actin cytoskeleton organization. Nat. Rev. Mol. Cell Biol., 2016, 17:799-810

[103] Suda T, Nakamura I, Jimi E, Takahashi N. Regulation of osteoclast function. J. Bone Min. Res., 1997, 12:869-879

[104] Henriksen K, Bollerslev J, Everts V, Karsdal MA. Osteoclast activity and subtypes as a function of physiology and pathology–implications for future treatments of osteoporosis. Endocr. Rev., 2011, 32:31-63

[105] Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J. Clin. Investig., 1992, 90:1622-1627

[106] Schwartzberg PL et al. Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice. Genes Dev., 1997, 11:2835-2844

[107] Pfaff M, Jurdic P. Podosomes in osteoclast-like cells: structural analysis and cooperative roles of paxillin, proline-rich tyrosine kinase 2 (Pyk2) and integrin alphaVbeta3. J. Cell Sci., 2001, 114:2775-2786

[108] Zhao H et al. Osteoprotegerin disrupts peripheral adhesive structures of osteoclasts by modulating Pyk2 and Src activities. Cell Adh. Migr., 2016, 10:299-309

[109] Kwon JO, Jin WJ, Kim B, Kim HH, Lee ZH. Myristoleic acid inhibits osteoclast formation and bone resorption by suppressing the RANKL activation of Src and Pyk2. Eur. J. Pharmacol., 2015, 768:189-198

[110] Gil-Henn H et al. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice. J. Cell Biol., 2007, 178:1053-1064

[111] Elsegood CL et al. M-CSF induces the stable interaction of cFms with alphaVbeta3 integrin in osteoclasts. Int J. Biochem. Cell Biol., 2006, 38:1518-1529

[112] Otero K et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat. Immunol., 2009, 10:734-743

[113] Stuart LM et al. CD36 signals to the actin cytoskeleton and regulates microglial migration via a p130Cas complex. J. Biol. Chem., 2007, 282:27392-27401

[114] Ganju RK et al. Beta-chemokine receptor CCR5 signals via the novel tyrosine kinase RAFTK. Blood, 1998, 91:791-797

[115] Janabi N, Peudenier S, Heron B, Ng KH, Tardieu M. Establishment of human microglial cell lines after transfection of primary cultures of embryonic microglial cells with the SV40 large T antigen. Neurosci. Lett., 1995, 195:105-108

[116] Premack BA, Schall TJ. Chemokine receptors: gateways to inflammation and infection. Nat. Med., 1996, 2:1174-1178

[117] Tian D, Litvak V, Lev S. Cerebral ischemia and seizures induce tyrosine phosphorylation of PYK2 in neurons and microglial cells. J. Neurosci., 2000, 20:6478-6487

[118] El Khoury JB et al. CD36 mediates the innate host response to beta-amyloid. J. Exp. Med, 2003, 197:1657-1666

[119] Cheung SM, Ostergaard HL. Pyk2 controls integrin-dependent CTL migration through regulation of de-adhesion. J. Immunol., 2016, 197:1945-1956

[120] Steblyanko M, Anikeeva N, Campbell KS, Keen JH, Sykulev Y. Integrins Influence the Size and Dynamics of Signaling Microclusters in a Pyk2-dependent Manner. J. Biol. Chem., 2015, 290:11833-11842

[121] Rosenberg HF, Phipps S, Foster PS. Eosinophil trafficking in allergy and asthma. J. Allergy Clin. Immunol., 2007, 119:1303-1310, quiz 1311–1312

[122] Duan Y et al. Inhibition of Pyk2 blocks airway inflammation and hyperresponsiveness in a mouse model of asthma. Am. J. Respir. Cell Mol. Biol., 2010, 42:491-497

[123] Zhu X et al. Proline-rich tyrosine kinase 2 regulates spreading and migration of eosinophils after beta2-integrin adhesion. Am. J. Respir. Cell Mol. Biol., 2008, 39:263-269

[124] Wang L, Learoyd J, Duan Y, Leff AR, Zhu X. Hematopoietic Pyk2 regulates migration of differentiated HL-60 cells. J. Inflamm., 2010, 7:26

[125] Anand AR et al. HIV-1 gp120-induced migration of dendritic cells is regulated by a novel kinase cascade involving Pyk2, p38 MAP kinase, and LSP1. Blood, 2009, 114:3588-3600

[126] Lambert JC et al. Meta-analysis of 74 046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet, 2013, 45:1452-1458

[127] Jansen IE et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet, 2019, 51:404-413

[128] Hou R et al. Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children. Bone, 2020, 132:115175

[129] Peacock M, Turner CH, Econs MJ, Foroud T. Genetics of osteoporosis. Endocr. Rev., 2002, 23:303-326

Funding

Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)(U01TR002623)

MEXT | Japan Society for the Promotion of Science (JSPS)(19K10044)