Abstract
The peripheral nervous system (PNS) has remarkable regenerative abilities after injury. Successful PNS regeneration relies on both injured axons and non-neuronal cells, including Schwann cells and immune cells. Macrophages are the most notable immune cells that play key roles in PNS injury and repair. Upon peripheral nerve injury, a large number of macrophages are accumulated at the injury sites, where they not only contribute to Wallerian degeneration, but also are educated by the local microenvironment and polarized to an anti-inflammatory phenotype (M2), thus contributing to axonal regeneration. Significant progress has been made in understanding how macrophages are educated and polarized in the injured microenvironment as well as how they contribute to axonal regeneration. Following the discussion on the main properties of macrophages and their phenotypes, in this review, we will summarize the current knowledge regarding the mechanisms of macrophage infiltration after PNS injury. Moreover, we will discuss the recent findings elucidating how macrophages are polarized to M2 phenotype in the injured PNS microenvironment, as well as the role and underlying mechanisms of macrophages in peripheral nerve injury, Wallerian degeneration and regeneration. Furthermore, we will highlight the potential application by targeting macrophages in treating peripheral nerve injury and peripheral neuropathies.
Similar content being viewed by others
References
Arthur-Farraj PJ, Latouche M, Wilton DK, Quintes S, Chabrol E, Banerjee A, Woodhoo A, Jenkins B, Rahman M, Turmaine M, Wicher GK, Mitter R, Greensmith L, Behrens A, Raivich G, Mirsky R, Jessen KR (2012) c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 75:633–647
Avellino AM, Dailey AT, Harlan JM, Sharar SR, Winn RK, McNutt LD, Kliot M (2004) Blocking of up-regulated ICAM-1 does not prevent macrophage infiltration during Wallerian degeneration of peripheral nerve. Exp Neurol 187:430–444
Baitsch D, Bock HH, Engel T, Telgmann R, Müller-Tidow C, Varga G, Bot M, Herz J, Robenek H, von Eckardstein A, Nofer JR (2011) Apolipoprotein E induces antiinflammatory phenotype in macrophages. Arterioscler Thromb Vasc Biol 31:1160–1168
Barrette B, Hébert MA, Filali M, Lafortune K, Vallières N, Gowing G, Julien JP, Lacroix S (2008) Requirement of myeloid cells for axon regeneration. J Neurosci 28:9363–9376
Bendszus M, Stoll G (2003) Caught in the act: in vivo mapping of macrophage infiltration in nerve injury by magnetic resonance imaging. J Neurosci 23:10892–10896
Benowitz LI, Popovich PG (2011) Inflammation and axon regeneration. Curr Opin Neurol 24:577–583
Beuche W, Friede RL (1986) Myelin phagocytosis in Wallerian degeneration of peripheral nerves depends on silica-sensitive, bg/bg-negative and Fc-positive monocytes. Brain Res 378:97–106
Bianco C, Gotze O, Cohn ZA (1979) Regulation of macrophage migration by products of the complement system. Proc Natl Acad Sci USA 76:888–891
Boivin A, Pineau I, Barrette B, Filali M, Vallières N, Rivest S, Lacroix S (2007) Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci 27:12565–12576
Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF (2012) Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 33:3792–3802
Brown HC, Castaño A, Fearn S, Townsend M, Edwards G, Streuli C, Perry VH (1997) Adhesion molecules involved in macrophage responses to Wallerian degeneration in the murine peripheral nervous system. Eur J Neurosci 9:2057–2063
Bruck W (1997) The role of macrophages in Wallerian degeneration. Brain Pathol 7:741–752
Bruck W, Bruck Y, Friede RL (1992) TNF-alpha suppresses CR3-mediated myelin removal by macrophages. J Neuroimmunol 38:9–17
Bruck W, Friede RL (1991) The role of complement in myelin phagocytosis during PNS wallerian degeneration. J Neurol Sci 103:182–187
Bruck W, Friede RL (1990) Anti-macrophage CR3 antibody blocks myelin phagocytosis by macrophages in vitro. Acta Neuropathol 80:415–418
Camara-Lemarroy CR, Guzman-de la Garza FJ, Fernandez-Garza NE (2010) Molecular inflammatory mediators in peripheral nerve degeneration and regeneration. Neuroimmunomodulation 17:314–324
Castano A, Bell MD, Perry VH (1996) Unusual aspects of inflammation in the nervous system: Wallerian degeneration. Neurobiol Aging 17:745–751
Cattin AL, Burden JJ, Van Emmenis L, Mackenzie FE, Hoving JJ, Garcia Calavia N, Guo Y, McLaughlin M, Rosenberg LH, Quereda V, Jamecna D, Napoli I, Parrinello S, Enver T, Ruhrberg C, Lloyd AC (2015) Macrophage-induced blood vessels guide schwann cell-mediated regeneration of peripheral nerves. Cell 162:1127–1139
Chen P, Bonaldo P (2013) Role of macrophage polarization in tumor angiogenesis and vessel normalization: implications for new anticancer therapies. Int Rev Cell Mol Biol 301:1–35
Chen P, Cescon M, Megighian A, Bonaldo P (2014) Collagen VI regulates peripheral nerve myelination and function. FASEB J 28:1145–1156
Chen P, Cescon M, Zuccolotto G, Nobbio L, Colombelli C, Filaferro M, Vitale G, Feltri ML, Bonaldo P (2015) Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization. Acta Neuropathol 129:97–113
Chen ZL, Yu WM, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233
Chernov AV, Dolkas J, Hoang K, Angert M, Srikrishna G, Vogl T, Baranovskaya S, Strongin AY, Shubayev VI (2015) The Calcium-binding proteins S100A8 and S100A9 initiate the early inflammatory program in injured peripheral nerves. J Biol Chem 290:11771–11784
Cote SC, Pasvanis S, Bounou S, Dumais N (2009) CCR7-specific migration to CCL19 and CCL21 is induced by PGE(2) stimulation in human monocytes: involvement of EP(2)/EP(4) receptors activation. Mol Immunol 46:2682–2693
Dailey AT, Avellino AM, Benthem L, Silver J, Kliot M (1998) Complement depletion reduces macrophage infiltration and activation during Wallerian degeneration and axonal regeneration. J Neurosci 18:6713–6722
de Jonge RR, van Schaik IN, Vreijling JP, Troost D, Baas F (2004) Expression of complement components in the peripheral nervous system. Hum Mol Genet 13:295–302
Dessing MC, Tammaro A, Pulskens WP, Teske GJ, Butter LM, Claessen N, van Eijk M, van der Poll T, Vogl T, Roth J, Florquin S, Leemans JC (2015) The calcium-binding protein complex S100A8/A9 has a crucial role in controlling macrophage-mediated renal repair following ischemia/reperfusion. Kidney Int 87:85–94
Diaz-Munoz MD, Osma-Garcia IC, Iniguez MA, Fresno M (2013) Cyclooxygenase-2 deficiency in macrophages leads to defective p110gamma PI3K signaling and impairs cell adhesion and migration. J Immunol 191:395–406
Doulatov S, Notta F, Eppert K, Nguyen LT, Ohashi PS, Dick JE (2010) Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nat Immunol 11:585–593
Dubovy P (2011) Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction. Ann Anat 193:267–275
Ehrchen JM, Sunderkotter C, Foell D, Vogl T, Roth J (2009) The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 86:557–566
Ferrante CJ, Leibovich SJ (2012) Regulation of macrophage polarization and wound healing. Adv Wound Care (New Rochelle) 1:10–16
Ferrante CJ, Pinhal-Enfield G, Elson G, Cronstein BN, Hasko G, Outram S, Leibovich SJ (2013) The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Ralpha) signaling. Inflammation 36:921–931
Francesco-Lisowitz A, Lindborg JA, Niemi JP, Zigmond RE (2015) The neuroimmunology of degeneration and regeneration in the peripheral nervous system. Neuroscience 302:174–203
Franco R, Fernandez-Suarez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 131:65–86
Galli SJ, Borregaard N, Wynn TA (2011) Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 12:1035–1044
Gaudet AD, Leung M, Poirier F, Kadoya T, Horie H, Ramer MS (2009) A role for galectin-1 in the immune response to peripheral nerve injury. Exp Neurol 220:320–327
Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 8:110
Gomez PE, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551
Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964
Gray M, Palispis W, Popovich PG, van Rooijen N, Gupta R (2007) Macrophage depletion alters the blood–nerve barrier without affecting Schwann cell function after neural injury. J Neurosci Res 85:766–777
Griffin JW, George R, Ho T (1993) Macrophage systems in peripheral nerves. A review. J Neuropathol Exp Neurol 52:553–560
Hack CE, Wolbink GJ, Schalkwijk C, Speijer H, Hermens WT, van den Bosch H (1997) A role for secretory phospholipase A2 and C-reactive protein in the removal of injured cells. Immunol Today 18:111–115
Hikawa N, Takenaka T (1996) Myelin-stimulated macrophages release neurotrophic factors for adult dorsal root ganglion neurons in culture. Cell Mol Neurobiol 16:517–528
Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375
Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10:1349–1355
Horie H, Kadoya T, Hikawa N, Sango K, Inoue H, Takeshita K, Asawa R, Hiroi T, Sato M, Yoshioka T, Ishikawa Y (2004) Oxidized galectin-1 stimulates macrophages to promote axonal regeneration in peripheral nerves after axotomy. J Neurosci 24:1873–1880
Huang JK, Phillips GR, Roth AD, Pedraza L, Shan W, Belkaid W, Mi S, Fex-Svenningsen A, Florens L, Yates JR 3rd, Colman DR (2005) Glial membranes at the node of Ranvier prevent neurite outgrowth. Science 310:1813–1817
Jang SY, Shin YK, Lee HY, Park JY, Suh DJ, Kim JK, Bae YS, Park HT (2012) Local production of serum amyloid a is implicated in the induction of macrophage chemoattractants in Schwann cells during wallerian degeneration of peripheral nerves. Glia 60:1619–1628
Kallenborn-Gerhardt W, Hohmann SW, Syhr KM, Schröder K, Sisignano M, Weigert A, Lorenz JE, Lu R, Brüne B, Brandes RP, Geisslinger G, Schmidtko A (2014) Nox2-dependent signaling between macrophages and sensory neurons contributes to neuropathic pain hypersensitivity. Pain 155:2161–2170
Keilhoff G, Langnaese K, Wolf G, Fansa H (2007) Inhibiting effect of minocycline on the regeneration of peripheral nerves. Dev Neurobiol 67:1382–1395
Kiguchi N, Kobayashi Y, Saika F, Kishioka S (2013) Epigenetic upregulation of CCL2 and CCL3 via histone modifications in infiltrating macrophages after peripheral nerve injury. Cytokine 64:666–672
Kiguchi N, Kobayashi Y, Saika F, Sakaguchi H, Maeda T, Kishioka S (2015) Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain. Pain 156:684–693
Kim D, You B, Lim H, Lee SJ (2011) Toll-like receptor 2 contributes to chemokine gene expression and macrophage infiltration in the dorsal root ganglia after peripheral nerve injury. Mol Pain 7:74
Kim Y, Remacle AG, Chernov AV, Liu H, Shubayev I, Lai C, Dolkas J, Shiryaev SA, Golubkov VS, Mizisin AP, Strongin AY, Shubayev VI (2012) The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration. PLoS One 7:e33664
Konofaos P, Terzis JK (2013) FK506 and nerve regeneration: past, present, and future. J Reconstr Microsurg 29:141–148
Kvist M, Danielsen N, Dahlin LB (2003) Effects of FK506 on regeneration and macrophages in injured rat sciatic nerve. J Peripher Nerv Syst 8:251–259
Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG, Lindemann RK, Marini P, Wiedig C, Zobywalski A, Baksh S, Xu Y, Autenrieth IB, Schulze-Osthoff K, Belka C, Stuhler G, Wesselborg S (2003) Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113:717–730
Lee HK, Shin YK, Jung J, Seo SY, Baek SY, Park HT (2009) Proteasome inhibition suppresses Schwann cell dedifferentiation in vitro and in vivo. Glia 57:1825–1834
Lee HY, Kim MK, Park KS, Shin EH, Jo SH, Kim SD, Jo EJ, Lee YN, Lee C, Baek SH, Bae YS (2006) Serum amyloid A induces contrary immune responses via formyl peptide receptor-like 1 in human monocytes. Mol Pharmacol 70:241–248
Lee HY, Kim SD, Shim JW, Lee SY, Lee H, Cho KH, Yun J, Bae YS (2008) Serum amyloid A induces CCL2 production via formyl peptide receptor-like 1-mediated signaling in human monocytes. J Immunol 181:4332–4339
Liou JT, Lee CM, Lin YC, Chen CY, Liao CC, Lee HC, Day YJ (2013) P-selectin is required for neutrophils and macrophage infiltration into injured site and contributes to generation of behavioral hypersensitivity following peripheral nerve injury in mice. Pain 154:2150–2159
Liou JT, Liu FC, Mao CC, Lai YS, Day YJ (2011) Inflammation confers dual effects on nociceptive processing in chronic neuropathic pain model. Anesthesiology 114:660–672
Liu T, van Rooijen N, Tracey DJ (2000) Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain 86:25–32
Lu X, Richardson PM (1993) Responses of macrophages in rat dorsal root ganglia following peripheral nerve injury. J Neurocytol 22:334–341
Malik RK, Ghurye RR, Lawrence-Watt DJ, Stewart HJ (2009) Galectin-1 stimulates monocyte chemotaxis via the p44/42 MAP kinase pathway and a pertussis toxin-sensitive pathway. Glycobiology 19:1402–1407
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555
Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13
Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461
Martini R, Fischer S, Lopez-Vales R, David S (2008) Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease. Glia 56:1566–1577
Moalem G, Tracey DJ (2006) Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 51:240–264
Mokarram N, Merchant A, Mukhatyar V, Patel G, Bellamkonda RV (2012) Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials 33:8793–8801
Mueller M, Leonhard C, Wacker K, Ringelstein EB, Okabe M, Hickey WF, Kiefer R (2003) Macrophage response to peripheral nerve injury: the quantitative contribution of resident and hematogenous macrophages. Lab Invest 83:175–185
Mueller M, Wacker K, Ringelstein EB, Hickey WF, Imai Y, Kiefer R (2001) Rapid response of identified resident endoneurial macrophages to nerve injury. Am J Pathol 159:2187–2197
Murinson BB, Archer DR, Li Y, Griffin JW (2005) Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents. J Neurosci 25:1179–1187
Myers RR, Heckman HM, Rodriguez M (1996) Reduced hyperalgesia in nerve-injured WLD mice: relationship to nerve fiber phagocytosis, axonal degeneration, and regeneration in normal mice. Exp Neurol 141:94–101
Nadeau S, Filali M, Zhang J, Kerr BJ, Rivest S, Soulet D, Iwakura Y, de Rivero Vaccari JP, Keane RW, Lacroix S (2011) Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1beta and TNF: implications for neuropathic pain. J Neurosci 31:12533–12542
Namikawa K, Fukushima M, Murakami K, Suzuki A, Takasawa S, Okamoto H, Kiyama H (2005) Expression of Reg/PAP family members during motor nerve regeneration in rat. Biochem Biophys Res Commun 332:126–134
Namikawa K, Okamoto T, Suzuki A, Konishi H, Kiyama H (2006) Pancreatitis-associated protein-III is a novel macrophage chemoattractant implicated in nerve regeneration. J Neurosci 26:7460–7467
Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S, Rosenberg LH, Collins MJ, Harrisingh MC, White IJ, Woodhoo A, Lloyd AC (2012) A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73:729–742
Nicol LS, Dawes JM, La RF, Didangelos A, Clark AK, Gentry C, Grist J, Davies JB, Malcangio M, McMahon SB (2015) The role of G-protein receptor 84 in experimental neuropathic pain. J Neurosci 35:8959–8969
Niemi JP, Francesco-Lisowitz A, Roldan-Hernandez L, Lindborg JA, Mandell D, Zigmond RE (2013) A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve regeneration. J Neurosci 33:16236–16248
Painter MW, Brosius LA, Cheng YC, Latremoliere A, Duong K, Miller CM, Posada S, Cobos EJ, Zhang AX, Wagers AJ, Havton LA, Barres B, Omura T, Woolf CJ (2014) Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration. Neuron 83:331–343
Parrinello S, Napoli I, Ribeiro S, Wingfield Digby P, Fedorova M, Parkinson DB, Doddrell RD, Nakayama M, Adams RH, Lloyd AC (2010) EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell 143:145–155
Perrin FE, Lacroix S, viles-Trigueros M, David S (2005) Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin-1beta in Wallerian degeneration. Brain 128:854–866
Perry VH, Brown MC (1992) Role of macrophages in peripheral nerve degeneration and repair. BioEssays 14:401–406
Perry VH, Brown MC, Gordon S (1987) The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration. J Exp Med 165:1218–1223
Popiolek-Barczyk K, Kolosowska N, Piotrowska A, Makuch W, Rojewska E, Jurga AM, Pilat D, Mika J (2015) Parthenolide relieves pain and promotes M2 microglia/macrophage polarization in rat model of neuropathy. Neural Plast 2015:676473
Potas JR, Haque F, Maclean FL, Nisbet DR (2015) Interleukin-10 conjugated electrospun polycaprolactone (PCL) nanofibre scaffolds for promoting alternatively activated (M2) macrophages around the peripheral nerve in vivo. J Immunol Methods 420:38–49
Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15:300–312
Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272
Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51
Ramaglia V, Wolterman R, de Kok M, Vigar MA, Wagenaar-Bos I, King RH, Morgan BP, Baas F (2008) Soluble complement receptor 1 protects the peripheral nerve from early axon loss after injury. Am J Pathol 172:1043–1052
Ristoiu V (2013) Contribution of macrophages to peripheral neuropathic pain pathogenesis. Life Sci 93:870–881
Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Åkerud P, De Mol M, Salomäki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44
Rosenberg AF, Wolman MA, Franzini-Armstrong C, Granato M (2012) In vivo nerve-macrophage interactions following peripheral nerve injury. J Neurosci 32:3898–3909
Rotshenker S (2011) Wallerian degeneration: the innate-immune response to traumatic nerve injury. J Neuroinflammation 8:109
Ruffell B, Coussens LM (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27:462–472
Saada A, Dunaevsky-Hutt A, Aamar A, Reichert F, Rotshenker S (1995) Fibroblasts that reside in mouse and frog injured peripheral nerves produce apolipoproteins. J Neurochem 64:1996–2003
Scheidt P, Friede RL (1987) Myelin phagocytosis in Wallerian degeneration. Properties of millipore diffusion chambers and immunohistochemical identification of cell populations. Acta Neuropathol 75:77–84
Schiopu A, Cotoi OS (2013) S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. Mediators Inflamm 2013:828354
Schreiber RC, Krivacic K, Kirby B, Vaccariello SA, Wei T, Ransohoff RM, Zigmond RE (2001) Monocyte chemoattractant protein (MCP)-1 is rapidly expressed by sympathetic ganglion neurons following axonal injury. NeuroReport 12:601–606
Schreiber RC, Shadiack AM, Bennett TA, Sedwick CE, Zigmond RE (1995) Changes in the macrophage population of the rat superior cervical ganglion after postganglionic nerve injury. J Neurobiol 27:141–153
Schuh CD, Pierre S, Weigert A, Weichand B, Altenrath K, Schreiber Y, Ferreiros N, Zhang DD, Suo J, Treutlein EM, Henke M, Kunkel H, Grez M, Nüsing R, Brüne B, Geisslinger G, Scholich K (2014) Prostacyclin mediates neuropathic pain through interleukin 1beta-expressing resident macrophages. Pain 155:545–555
Schulz C, Schafer A, Stolla M, Kerstan S, Lorenz M, von Brühl ML, Schiemann M, Bauersachs J, Gloe T, Busch DH, Gawaz M, Massberg S (2007) Chemokine fractalkine mediates leukocyte recruitment to inflammatory endothelial cells in flowing whole blood: a critical role for P-selectin expressed on activated platelets. Circulation 116:764–773
Seitz RJ, Reiners K, Himmelmann F, Heininger K, Hartung HP, Toyka KV (1989) The blood-nerve barrier in Wallerian degeneration: a sequential long-term study. Muscle Nerve 12:627–635
Semple JW, Freedman J (2010) Platelets and innate immunity. Cell Mol Life Sci 67:499–511
Shamash S, Reichert F, Rotshenker S (2002) The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci 22:3052–3060
Siebert H, Dippel N, Mader M, Weber F, Weber F, Brück W (2001) Matrix metalloproteinase expression and inhibition after sciatic nerve axotomy. J Neuropathol Exp Neurol 60:85–93
Siebert H, Sachse A, Kuziel WA, Maeda N, Bruck W (2000) The chemokine receptor CCR2 is involved in macrophage recruitment to the injured peripheral nervous system. J Neuroimmunol 110:177–185
Sierra-Filardi E, Nieto C, Dominguez-Soto A, Barroso R, Sanchez-Mateos P, Puig-Kroger A, Lopez-Bravo M, Joven J, Ardavin C, Rodríguez-Fernandez JL, Sanchez-Torres C, Mellado M, Corbi AL (2014) CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile. J Immunol 192:3858–3867
Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, Orenstein JM, Smith PD (2005) Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 115:66–75
Snipes GJ, McGuire CB, Norden JJ, Freeman JA (1986) Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells. Proc Natl Acad Sci USA 83:1130–1134
Sommer C, Schafers M (1998) Painful mononeuropathy in C57BL/Wld mice with delayed wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. Brain Res 784:154–162
Stoll G, Muller HW (1999) Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol 9:313–325
Tanaka T, Minami M, Nakagawa T, Satoh M (2004) Enhanced production of monocyte chemoattractant protein-1 in the dorsal root ganglia in a rat model of neuropathic pain: possible involvement in the development of neuropathic pain. Neurosci Res 48:463–469
Taskinen HS, Roytta M (1997) The dynamics of macrophage recruitment after nerve transection. Acta Neuropathol 93:252–259
Tchernychev B, Furie B, Furie BC (2003) Peritoneal macrophages express both P-selectin and PSGL-1. J Cell Biol 163:1145–1155
Toews AD, Barrett C, Morell P (1998) Monocyte chemoattractant protein 1 is responsible for macrophage recruitment following injury to sciatic nerve. J Neurosci Res 53:260–267
Tofaris GK, Patterson PH, Jessen KR, Mirsky R (2002) Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 22:6696–6703
Uhlar CM, Whitehead AS (1999) Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265:501–523
Van SJ, Auvynet C, Sapienza A, Reaux-Le Goazigo A, Combadiere C, Melik Parsadaniantz S (2015) Stromal cell-derived CCL2 drives neuropathic pain states through myeloid cell infiltration in injured nerve. Brain Behav Immun 45:198–210
Vargas ME, Watanabe J, Singh SJ, Robinson WH, Barres BA (2010) Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury. Proc Natl Acad Sci USA 107:11993–11998
Vougioukas VI, Roeske S, Michel U, Bruck W (1998) Wallerian degeneration in ICAM-1-deficient mice. Am J Pathol 152:241–249
Yang J, Gu Y, Huang X, Shen A, Cheng C (2011) Dynamic changes of ICAM-1 expression in peripheral nervous system following sciatic nerve injury. Neurol Res 33:75–83
Ydens E, Cauwels A, Asselbergh B, Goethals S, Peeraer L, Lornet G, Almeida-Souza L, Van Ginderachter JA, Timmerman V, Janssens S (2012) Acute injury in the peripheral nervous system triggers an alternative macrophage response. J Neuroinflammation 9:176
Zhang L, Johnson D, Johnson JA (2013) Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury. Neurobiol Dis 54:329–338
Acknowledgments
We apologize to all these authors whose papers we could not cite due to space limitations. This work was supported by the University of Padova and the Italian Ministry of Education. P. Chen was supported by a fellowship from the Cariparo Foundation.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no potential conflicts of interest.
Rights and permissions
About this article
Cite this article
Chen, P., Piao, X. & Bonaldo, P. Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. Acta Neuropathol 130, 605–618 (2015). https://doi.org/10.1007/s00401-015-1482-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-015-1482-4