CD300f immunoreceptor contributes to peripheral nerve regeneration by the modulation of macrophage inflammatory phenotype

Journal of Neuroinflammation

Natalia Lago⁴  Joan Sayós⁵  Ruben López-Vales³  Xavier Navarro³  Isaac Francos-Quijorna³  Maria Luciana Negro-Demontel²  Patricia Solari-Saquieres²  Hugo Peluffo¹ 

[1] Department of Histology and Embryology, Faculty of Medicine, UDELAR, Montevideo, Uruguay;Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur Montevideo, Mataojo 2020, Montevideo, CP 11400, Uruguay;Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain;Neurodegeneration Laboratory, Institut Pasteur Montevideo, Montevideo, Uruguay;Immunobiology Group, CIBBIM-Nanomedicine Program, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain

关键词: Phagocytosis;    Wallerian degeneration;    Schwann cell;    Macrophage M1/M2 phenotype;    CD300;    Immunoreceptors;    Regeneration;   

Others  :  1227082
DOI  :  10.1186/s12974-015-0364-y

 received in 2015-02-10, accepted in 2015-07-21,  发布年份 2015

【 摘 要 】

Background

It has recently become evident that activating/inhibitory cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). The immunoreceptor CD300f expressed on monocytes, neutrophils, and mast cells modulates inflammation, phagocytosis, and outcome in models of autoimmune demyelination, allergy, and systemic lupus erythematosus. On the other hand, a finely regulated inflammatory response is essential to induce regeneration after injury to peripheral nerves since hematogenous macrophages, together with resident macrophages and de-differentiated Schwann cells, phagocyte distal axonal and myelin debris in a well-orchestrated inflammatory response. The possible roles and expression of CD300f and its ligands have not been reported under these conditions.

Methods

By using quantitative PCR (QPCR) and CD300f-IgG2a fusion protein, we show the expression of CD300f and its ligands in the normal and crush injured sciatic nerve. The putative role of CD300f in peripheral nerve regeneration was analyzed by blocking receptor-ligand interaction with the same CD300f-IgG2a soluble receptor fusion protein in sciatic nerves of Thy1-YFP-H mice injected at the time of injury. Macrophage M1/M2 polarization phenotype was also analyzed by CD206 and iNOS expression.

Results

We found an upregulation of CD300f mRNA and protein expression after injury. Moreover, the ligands are present in restricted membrane patches of Schwann cells, which remain stable after the lesion. The lesioned sciatic nerves of Thy1-YFP-H mice injected with a single dose of CD300f-IgG2a show long lasting effects on nerve regeneration characterized by a lower number of YFP-positive fibres growing into the tibial nerve after 10 days post lesion (dpl) and a delayed functional recovery when compared to PBS- or IgG2a-administered control groups. Animals treated with CD300f-IgG2a show at 10 dpl higher numbers of macrophages and CD206-positive cells and lower levels of iNOS expression than both control groups. At later time points (28 dpl), increased numbers of macrophages and iNOS expression occur.

Conclusions

Taken together, these results show that the pair CD300f ligand is implicated in Wallerian degeneration and nerve regeneration by modulating both the influx and phenotype of macrophages.

【 授权许可】

   
2015 Peluffo et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

【 参考文献 】

• [1]Lago N, Navarro X: Correlation between target reinnervation and distribution of motor axons in the injured rat sciatic nerve. J Neurotrauma 2006, 23:227-240.
• [2]Deumens R, Bozkurt A, Meek MF, Marcus MA, Joosten EA, Weis J, Brook GA: Repairing injured peripheral nerves: bridging the gap. Prog Neurobiol 2010, 92:245-276.
• [3]Allodi I, Udina E, Navarro X: Specificity of peripheral nerve regeneration: interactions at the axon level. Prog Neurobiol 2012, 98:16-37.
• [4]Waller A: Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, observations of the alterations produced thereby in the structure of their primitive fibers. Phil Transact Royal Soc London 1850, 140:423-429.
• [5]Vargas ME, Barres BA: Why is Wallerian degeneration in the CNS so slow? Annu Rev Neurosci 2007, 30:153-179.
• [6]Schafer M, Fruttiger M, Montag D, Schachner M, Martini R: Disruption of the gene for the myelin-associated glycoprotein improves axonal regrowth along myelin in C57BL/Wlds mice. Neuron 1996, 16:1107-1113.
• [7]Fruttiger M, Montag D, Schachner M, Martini R: Crucial role for the myelin-associated glycoprotein in the maintenance of axon-myelin integrity. Eur J Neurosci 1995, 7:511-515.
• [8]Gaudet AD, Popovich PG, Ramer MS: Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 2011, 8:110. BioMed Central Full Text
• [9]Rotshenker S: Wallerian degeneration: the innate-immune response to traumatic nerve injury. J Neuroinflammation 2011, 8:109. BioMed Central Full Text
• [10]Avellino AM, Hart D, Dailey AT, MacKinnon M, Ellegala D, Kliot M: Differential macrophage responses in the peripheral and central nervous system during Wallerian degeneration of axons. Exp Neurol 1995, 136:183-198.
• [11]Omura T, Omura K, Sano M, Sawada T, Hasegawa T, Nagano A: Spatiotemporal quantification of recruit and resident macrophages after crush nerve injury utilizing immunohistochemistry. Brain Res 2005, 1057:29-36.
• [12]Be’eri H, Reichert F, Saada A, Rotshenker S: The cytokine network of Wallerian degeneration: IL-10 and GM-CSF. Eur J Neurosci 1998, 10:2707-2713.
• [13]Shamash S, Reichert F, Rotshenker S: The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci 2002, 22:3052-3060.
• [14]Sawada T, Sano M, Omura T, Omura K, Hasegawa T, Funahashi S, Nagano A: Spatiotemporal quantification of tumor necrosis factor-alpha and interleukin-10 after crush injury in rat sciatic nerve utilizing immunohistochemistry. Neurosci Lett 2007, 417:55-60.
• [15]Liefner M, Siebert H, Sachse T, Michel U, Kollias G, Bruck W: The role of TNF-alpha during Wallerian degeneration. J Neuroimmunol 2000, 108:147-152.
• [16]George A, Kleinschnitz C, Zelenka M, Brinkhoff J, Stoll G, Sommer C: Wallerian degeneration after crush or chronic constriction injury of rodent sciatic nerve is associated with a depletion of endoneurial interleukin-10 protein. Exp Neurol 2004, 188:187-191.
• [17]Gordon S: Alternative activation of macrophages. Nat Rev Immunol 2003, 3:23-35.
• [18]Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K: Development of monocytes, macrophages, and dendritic cells. Science 2010, 327:656-661.
• [19]Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M: The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004, 25:677-686.
• [20]David S, Kroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011, 12:388-399.
• [21]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.
• [22]Ydens E, Cauwels A, Asselbergh B, Goethals S, Peeraer L, Lornet G, Almeida-Souza L, Van Ginderachter JA, Timmerman V, Janssens S: Acute injury in the peripheral nervous system triggers an alternative macrophage response. J Neuroinflammation 2012, 9:176. BioMed Central Full Text
• [23]Mokarram N, Merchant A, Mukhatyar V, Patel G, Bellamkonda RV: Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials 2012, 33:8793-8801.
• [24]Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, et al.: Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 2000, 290:1768-1771.
• [25]Neumann H, Takahashi K: Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J Neuroimmunol 2007, 184:92-99.
• [26]Alvarez-Errico D, Aguilar H, Kitzig F, Brckalo T, Sayos J, Lopez-Botet M: IREM-1 is a novel inhibitory receptor expressed by myeloid cells. Eur J Immunol 2004, 34:3690-3701.
• [27]Aguilar H, Alvarez-Errico D, Garcia-Montero AC, Orfao A, Sayos J, Lopez-Botet M: Molecular characterization of a novel immune receptor restricted to the monocytic lineage. J Immunol 2004, 173:6703-6711.
• [28]Alvarez-Errico D, Sayos J, Lopez-Botet M: The IREM-1 (CD300f) inhibitory receptor associates with the p85alpha subunit of phosphoinositide 3-kinase. J Immunol 2007, 178:808-816.
• [29]Comas-Casellas E, Martinez-Barriocanal A, Miro F, Ejarque-Ortiz A, Schwartz S Jr, Martin M, Sayos J: Cloning and characterization of CD300d, a novel member of the human CD300 family of immune receptors. J Biol Chem 2012, 287:9682-9693.
• [30]Martinez-Barriocanal A, Sayos J: Molecular and functional characterization of CD300b, a new activating immunoglobulin receptor able to transduce signals through two different pathways. J Immunol 2006, 177:2819-2830.
• [31]Borrego F: The CD300 molecules: an emerging family of regulators of the immune system. Blood 2013, 121(11):1951-60.
• [32]Martinez-Barriocanal A, Comas-Casellas E, Schwartz S Jr, Martin M, Sayos J: CD300 heterocomplexes, a new and family-restricted mechanism for myeloid cell signaling regulation. J Biol Chem 2010, 285:41781-41794.
• [33]Torres-Espin A, Hernandez J, Navarro X: Gene expression changes in the injured spinal cord following transplantation of mesenchymal stem cells or olfactory ensheathing cells. PLoS ONE 2013., 8Article ID e76141
• [34]Nielsen R, Bustamante C, Clark AG, Glanowski S, Sackton TB, Hubisz MJ, Fledel-Alon A, Tanenbaum DM, Civello D, White TJ, et al.: A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol 2005., 3Article ID e170
• [35]Choi SC, Simhadri VR, Tian L, Gil-Krzewska A, Krzewski K, Borrego F, Coligan JE: Cutting edge: mouse CD300f (CMRF-35-like molecule-1) recognizes outer membrane-exposed phosphatidylserine and can promote phagocytosis. J Immunol 2011, 187:3483-3487.
• [36]Tian L, Choi SC, Murakami Y, Allen J, Morse HC 3rd, Qi CF, Krzewski K, Coligan JE: p85alpha recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression. Nat Commun 2014, 5:3146.
• [37]Ejarque-Ortiz A, Sola C, Martinez-Barriocanal A, Schwartz S Jr, Martin M, Peluffo H, Sayos J: The receptor CMRF35-like molecule-1 (CLM-1) enhances the production of LPS-induced pro-inflammatory mediators during microglial activation. PLoS ONE 2015., 10Article ID e0123928
• [38]Moshkovits I, Karo-Atar D, Itan M, Reichman H, Rozenberg P, Morgenstern-Ben-Baruch N, Shik D, Ejarque-Ortiz A, Hershko AY, Tian L, et al.: CD300f associates with IL-4 receptor α and amplifies IL-4–induced immune cell responses. Proc Natl Acad Sci U S A 2015, 112(28):8708-13.
• [39]Xi H, Katschke KJ Jr, Helmy KY, Wark PA, Kljavin N, Clark H, Eastham-Anderson J, Shek T, Roose-Girma M, Ghilardi N, van Lookeren CM: Negative regulation of autoimmune demyelination by the inhibitory receptor CLM-1. J Exp Med 2010, 207:7-16.
• [40]Izawa K, Yamanishi Y, Maehara A, Takahashi M, Isobe M, Ito S, Kaitani A, Matsukawa T, Matsuoka T, Nakahara F, et al.: The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide. Immunity 2012, 37:827-839.
• [41]Cannon JP, O’Driscoll M, Litman GW: Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 2012, 64:39-47.
• [42]Izawa K, Isobe M, Matsukawa T, Ito S, Maehara A, Takahashi M, Yamanishi Y, Kaitani A, Oki T, Okumura K, et al.: Sphingomyelin and ceramide are physiological ligands for human LMIR3/CD300f, inhibiting FcepsilonRI-mediated mast cell activation. J Allergy Clin Immunol 2014, 133:270-273.
• [43]Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW, Sanes JR: Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 2000, 28:41-51.
• [44]Ale A, Bruna J, Morell M, van de Velde H, Monbaliu J, Navarro X, Udina E: Treatment with anti-TNF alpha protects against the neuropathy induced by the proteasome inhibitor bortezomib in a mouse model. Exp Neurol 2014, 253:165-173.
• [45]Klopstein A, Santos-Nogueira E, Francos-Quijorna I, Redensek A, David S, Navarro X, Lopez-Vales R: Beneficial effects of alphaB-crystallin in spinal cord contusion injury. J Neurosci 2012, 32:14478-14488.
• [46]Fricker FR, Lago N, Balarajah S, Tsantoulas C, Tanna S, Zhu N, Fageiry SK, Jenkins M, Garratt AN, Birchmeier C, Bennett DL: Axonally derived neuregulin-1 is required for remyelination and regeneration after nerve injury in adulthood. J Neurosci 2011, 31:3225-3233.
• [47]Bain JR, Mackinnon SE, Hunter DA: Functional evaluation of complete sciatic, peroneal, and posterior tibial nerve lesions in the rat. Plast Reconstr Surg 1989, 83:129-138.
• [48]Lopez-Vales R, Navarro X, Shimizu T, Baskakis C, Kokotos G, Constantinou-Kokotou V, Stephens D, Dennis EA, David S: Intracellular phospholipase A(2) group IVA and group VIA play important roles in Wallerian degeneration and axon regeneration after peripheral nerve injury. Brain 2008, 131:2620-2631.
• [49]Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001., 29Article ID e45
• [50]Peluffo H, Ali-Ruiz D, Ejarque-Ortiz A, Heras-Alvarez V, Comas-Casellas E, Martinez-Barriocanal A, Kamaid A, Alvarez-Errico D, Negro ML, Lago N, et al.: Overexpression of the immunoreceptor CD300f has a neuroprotective role in a model of acute brain injury. Brain Pathol 2011, 22:318-328.
• [51]Fricker FR, Zhu N, Tsantoulas C, Abrahamsen B, Nassar MA, Thakur M, Garratt AN, Birchmeier C, McMahon SB, Wood JN, Bennett DL: Sensory axon-derived neuregulin-1 is required for axoglial signaling and normal sensory function but not for long-term axon maintenance. J Neurosci 2009, 29:7667-7678.
• [52]Groves ML, McKeon R, Werner E, Nagarsheth M, Meador W, English AW: Axon regeneration in peripheral nerves is enhanced by proteoglycan degradation. Exp Neurol 2005, 195:278-292.
• [53]Beirowski B, Berek L, Adalbert R, Wagner D, Grumme DS, Addicks K, Ribchester RR, Coleman MP: Quantitative and qualitative analysis of Wallerian degeneration using restricted axonal labelling in YFP-H mice. J Neurosci Methods 2004, 134:23-35.
• [54]English AW, Meador W, Carrasco DI: Neurotrophin-4/5 is required for the early growth of regenerating axons in peripheral nerves. Eur J Neurosci 2005, 21:2624-2634.
• [55]Acarin L, Vela JM, Gonzalez B, Castellano B: Demonstration of poly-N-acetyl lactosamine residues in ameboid and ramified microglial cells in rat brain by tomato lectin binding. J Histochem Cytochem 1994, 42:1033-1041.
• [56]Peluffo H, Acarin L, Faiz M, Castellano B, Gonzalez B: Cu/Zn superoxide dismutase expression in the postnatal rat brain following an excitotoxic injury. J Neuroinflammation 2005, 2:12. BioMed Central Full Text
• [57]Phongsisay V, Iizasa E, Hara H, Yamasaki S: 3-O-sulfo-beta-d-galactose moiety of endogenous sulfoglycolipids is a potential ligand for immunoglobulin-like receptor LMIR5. Mol Immunol 2015, 63:595-599.
• [58]Court FA, Zambroni D, Pavoni E, Colombelli C, Baragli C, Figlia G, Sorokin L, Ching W, Salzer JL, Wrabetz L, Feltri ML: MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains. J Neurosci 2011, 31:12208-12217.
• [59]Chang CY, Lee YH, Jiang-Shieh YF, Chien HF, Pai MH, Chen HM, Fong TH, Wu CH: Novel distribution of cluster of differentiation 200 adhesion molecule in glial cells of the peripheral nervous system of rats and its modulation after nerve injury. Neuroscience 2011, 183:32-46.
• [60]Linnartz B, Wang Y, Neumann H. Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation. Int J Alzheimers Dis. 2010;2010.
• [61]Biber K, Neumann H, Inoue K, Boddeke HW: Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 2007, 30:596-602.
• [62]Ransohoff RM, Cardona AE: The myeloid cells of the central nervous system parenchyma. Nature 2010, 468:253-262.
• [63]Kim EJ, Lee SM, Suk K, Lee WH: CD300a and CD300f differentially regulate the MyD88 and TRIF-mediated TLR signalling pathways through activation of SHP-1 and/or SHP-2 in human monocytic cell lines. Immunology 2012, 135:226-235.
• [64]Mueller M, Leonhard C, Wacker K, Ringelstein EB, Okabe M, Hickey WF, Kiefer R: Macrophage response to peripheral nerve injury: the quantitative contribution of resident and hematogenous macrophages. Lab Invest 2003, 83:175-185.
• [65]Nadeau S, Filali M, Zhang J, Kerr BJ, Rivest S, Soulet D, Iwakura Y, de Rivero Vaccari JP, Keane RW, Lacroix S: Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1beta and TNF: implications for neuropathic pain. J Neurosci 2011, 31:12533-12542.