Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Nerve Injury | Research

M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast–Schwann cell-signaling relay

Authors: Eri Oshima, Yoshinori Hayashi, Zhen Xie, Hitoshi Sato, Suzuro Hitomi, Ikuko Shibuta, Kentaro Urata, Junjun Ni, Koichi Iwata, Tatsuo Shirota, Masamichi Shinoda

Published in: Journal of Neuroinflammation | Issue 1/2023

Login to get access

Abstract

Background

Although peripheral nerves have an intrinsic self-repair capacity following damage, functional recovery is limited in patients. It is a well-established fact that macrophages accumulate at the site of injury. Numerous studies indicate that the phenotypic shift from M1 macrophage to M2 macrophage plays a crucial role in the process of axon regeneration. This polarity change is observed exclusively in peripheral macrophages but not in microglia and CNS macrophages. However, the molecular basis of axonal regeneration by M2 macrophage is not yet fully understood. Herein, we aimed to identify the M2 macrophage-derived axon regeneration factor.

Methods

We established a peripheral nerve injury model by transection of the inferior alveolar nerve (IANX) in Sprague–Dawley rats. Transcriptome analysis was performed on the injured nerve. Recovery from sensory deficits in the mandibular region and histological reconnection of IAN after IANX were assessed in rats with macrophage depletion by clodronate. We investigated the effects of adoptive transfer of M2 macrophages or M2-derived cathepsin S (CTSS) on the sensory deficit. CTSS initiating signaling was explored by western blot analysis in IANX rats and immunohistochemistry in co-culture of primary fibroblasts and Schwann cells (SCs).

Results

Transcriptome analysis revealed that CTSS, a macrophage-selective lysosomal protease, was upregulated in the IAN after its injury. Spontaneous but partial recovery from a sensory deficit in the mandibular region after IANX was abrogated by macrophage ablation at the injured site. In addition, a robust induction of c-Jun, a marker of the repair-supportive phenotype of SCs, after IANX was abolished by macrophage ablation. As in transcriptome analysis, CTSS was upregulated at the injured IAN than in the intact IAN. Endogenous recovery from hypoesthesia was facilitated by supplementation of CTSS but delayed by pharmacological inhibition or genetic silencing of CTSS at the injured site. Adoptive transfer of M2-polarized macrophages at this site facilitated sensory recovery dependent on CTSS in macrophages. Post-IANX, CTSS caused the cleavage of Ephrin-B2 in fibroblasts, which, in turn, bound EphB2 in SCs. CTSS-induced Ephrin-B2 cleavage was also observed in human sensory nerves. Inhibition of CTSS-induced Ephrin-B2 signaling suppressed c-Jun induction in SCs and sensory recovery.

Conclusions

These results suggest that M2 macrophage-derived CTSS contributes to axon regeneration by activating SCs via Ephrin-B2 shedding from fibroblasts.
Appendix
Available only for authorised users
Literature
1.
2.
Rosenzweig ES, Courtine G, Jindrich DL, Brock JH, Ferguson AR, Strand SC, Nout YS, Roy RR, Miller DM, Beattie MS, et al. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci. 2010;13:1505–10.PubMedPubMedCentralCrossRef
3.
4.
Tay AB, Zuniga JR. Clinical characteristics of trigeminal nerve injury referrals to a university centre. Int J Oral Maxillofac Surg. 2007;36:922–7.PubMedCrossRef
5.
Ozen T, Orhan K, Gorur I, Ozturk A. Efficacy of low level laser therapy on neurosensory recovery after injury to the inferior alveolar nerve. Head Face Med. 2006;2:3.PubMedPubMedCentralCrossRef
6.
Perrin FE, Lacroix S, Aviles-Trigueros M, David S. Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin-1beta in Wallerian degeneration. Brain. 2005;128:854–66.PubMedCrossRef
7.
Arthur-Farraj PJ, Latouche M, Wilton DK, Quintes S, Chabrol E, Banerjee A, Woodhoo A, Jenkins B, Rahman M, Turmaine M, et al. c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron. 2012;75:633–47.PubMedPubMedCentralCrossRef
8.
9.
Masuda T, Amann L, Monaco G, Sankowski R, Staszewski O, Krueger M, Del Gaudio F, He L, Paterson N, Nent E, et al. Specification of CNS macrophage subsets occurs postnatally in defined niches. Nature. 2022;604:740–8.PubMedCrossRef
10.
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;31:12533–42.PubMedPubMedCentralCrossRef
11.
Jia Y, Yang W, Zhang K, Qiu S, Xu J, Wang C, Chai Y. Nanofiber arrangement regulates peripheral nerve regeneration through differential modulation of macrophage phenotypes. Acta Biomater. 2019;83:291–301.PubMedCrossRef
12.
Huang TC, Wu HL, Chen SH, Wang YT, Wu CC. Thrombomodulin facilitates peripheral nerve regeneration through regulating M1/M2 switching. J Neuroinflammation. 2020;17:240.PubMedPubMedCentralCrossRef
13.
Chen P, Cescon M, Zuccolotto G, Nobbio L, Colombelli C, Filaferro M, Vitale G, Feltri ML, Bonaldo P. Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization. Acta Neuropathol. 2015;129:97–113.PubMedCrossRef
14.
Barrette B, Hebert MA, Filali M, Lafortune K, Vallieres N, Gowing G, Julien JP, Lacroix S. Requirement of myeloid cells for axon regeneration. J Neurosci. 2008;28:9363–76.PubMedPubMedCentralCrossRef
15.
Liu T, van Rooijen N, Tracey DJ. Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain. 2000;86:25–32.PubMedCrossRef
16.
Benito C, Davis CM, Gomez-Sanchez JA, Turmaine M, Meijer D, Poli V, Mirsky R, Jessen KR. STAT3 controls the long-term survival and phenotype of repair schwann cells during nerve regeneration. J Neurosci. 2017;37:4255–69.PubMedPubMedCentralCrossRef
17.
Fontana X, Hristova M, Da Costa C, Patodia S, Thei L, Makwana M, Spencer-Dene B, Latouche M, Mirsky R, Jessen KR, et al. c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling. J Cell Biol. 2012;198:127–41.PubMedPubMedCentralCrossRef
18.
Mindos T, Dun XP, North K, Doddrell RD, Schulz A, Edwards P, Russell J, Gray B, Roberts SL, Shivane A, et al. Merlin controls the repair capacity of Schwann cells after injury by regulating Hippo/YAP activity. J Cell Biol. 2017;216:495–510.PubMedPubMedCentralCrossRef
19.
Tofaris GK, Patterson PH, Jessen KR, Mirsky R. 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. 2002;22:6696–703.PubMedPubMedCentralCrossRef
20.
Brosius Lutz A, Chung WS, Sloan SA, Carson GA, Zhou L, Lovelett E, Posada S, Zuchero JB, Barres BA. Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury. Proc Natl Acad Sci U S A. 2017;114:E8072–80.PubMedPubMedCentralCrossRef
21.
Gomez-Sanchez JA, Carty L, Iruarrizaga-Lejarreta M, Palomo-Irigoyen M, Varela-Rey M, Griffith M, Hantke J, Macias-Camara N, Azkargorta M, Aurrekoetxea I, et al. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves. J Cell Biol. 2015;210:153–68.PubMedPubMedCentralCrossRef
22.
Cattin AL, Burden JJ, Van Emmenis L, Mackenzie FE, Hoving JJ, Garcia Calavia N, Guo Y, McLaughlin M, Rosenberg LH, Quereda V, et al. Macrophage-induced blood vessels guide schwann cell-mediated regeneration of peripheral nerves. Cell. 2015;162:1127–39.PubMedPubMedCentralCrossRef
23.
Stratton JA, Holmes A, Rosin NL, Sinha S, Vohra M, Burma NE, Trang T, Midha R, Biernaskie J. Macrophages regulate schwann cell maturation after nerve injury. Cell Rep. 2018;24(2561–2572): e2566.
24.
Wagstaff LJ, Gomez-Sanchez JA, Fazal SV, Otto GW, Kilpatrick AM, Michael K, Wong LYN, Ma KH, Turmaine M, Svaren J, et al. Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun. Elife 2021; 10.
25.
Jessen KR, Mirsky R. The role of c-jun and autocrine signaling loops in the control of repair schwann cells and regeneration. Front Cell Neurosci. 2021;15: 820216.PubMedCrossRef
26.
Parrinello S, Napoli I, Ribeiro S, Wingfield Digby P, Fedorova M, Parkinson DB, Doddrell RD, Nakayama M, Adams RH, Lloyd AC. EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell. 2010;143:145–55.PubMedCrossRef
27.
28.
Petanceska S, Canoll P, Devi LA. Expression of rat cathepsin S in phagocytic cells. J Biol Chem. 1996;271:4403–9.PubMedCrossRef
29.
Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci U S A. 2007;104:10655–60.PubMedPubMedCentralCrossRef
30.
Hayashi Y, Koyanagi S, Kusunose N, Okada R, Wu Z, Tozaki-Saitoh H, Ukai K, Kohsaka S, Inoue K, Ohdo S, Nakanishi H. The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S. Sci Rep. 2013;3:2744.PubMedPubMedCentralCrossRef
31.
Lagares D, Ghassemi-Kakroodi P, Tremblay C, Santos A, Probst CK, Franklin A, Santos DM, Grasberger P, Ahluwalia N, Montesi SB, et al. ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nat Med. 2017;23:1405–15.PubMedPubMedCentralCrossRef
32.
Jin YQ, Liu W, Hong TH, Cao Y. Efficient Schwann cell purification by differential cell detachment using multiplex collagenase treatment. J Neurosci Methods. 2008;170:140–8.PubMedCrossRef
33.
Watabe K, Fukuda T, Tanaka J, Toyohara K, Sakai O. Mitogenic effects of platelet-derived growth factor, fibroblast growth factor, transforming growth factor-beta, and heparin-binding serum factor for adult mouse Schwann cells. J Neurosci Res. 1994;39:525–34.PubMedCrossRef
34.
Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015;33:290–5.PubMedPubMedCentralCrossRef
35.
Rouillard AD, Gundersen GW, Fernandez NF, Wang Z, Monteiro CD, McDermott MG, Ma’ayan A. The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford) 2016; 2016.
36.
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.PubMedPubMedCentralCrossRef
37.
Ferdoushi A, Li X, Griffin N, Faulkner S, Jamaluddin MFB, Gao F, Jiang CC, van Helden DF, Tanwar PS, Jobling P, Hondermarck H. Schwann cell stimulation of pancreatic cancer cells: a proteomic analysis. Front Oncol. 2020;10:1601.PubMedPubMedCentralCrossRef
38.
Qin J, Zha GB, Yu J, Zhang HH, Yi S. Differential temporal expression of matrix metalloproteinases following sciatic nerve crush. Neural Regen Res. 2016;11:1165–71.PubMedPubMedCentralCrossRef
39.
Matsui Y, Kadoya K, Nagano Y, Endo T, Hara M, Matsumae G, Suzuki T, Yamamoto Y, Terkawi MA, Iwasaki N. IL4 stimulated macrophages promote axon regeneration after peripheral nerve injury by secreting uPA to stimulate uPAR upregulated in injured axons. Cell Mol Life Sci. 2022;79:289.PubMedCrossRef
40.
Ainscough JS, Macleod T, McGonagle D, Brakefield R, Baron JM, Alase A, Wittmann M, Stacey M. Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36gamma. Proc Natl Acad Sci U S A. 2017;114:E2748–57.PubMedPubMedCentralCrossRef
41.
Flynn CM, Garbers Y, Dusterhoft S, Wichert R, Lokau J, Lehmann CHK, Dudziak D, Schroder B, Becker-Pauly C, Rose-John S, et al. Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro. Sci Rep. 2020;10:21612.PubMedPubMedCentralCrossRef
42.
Dun XP, Carr L, Woodley PK, Barry RW, Drake LK, Mindos T, Roberts SL, Lloyd AC, Parkinson DB. Macrophage-derived slit3 controls cell migration and axon pathfinding in the peripheral nerve bridge. Cell Rep. 2019;26(1458–1472): e1454.
43.
Ydens E, Amann L, Asselbergh B, Scott CL, Martens L, Sichien D, Mossad O, Blank T, De Prijck S, Low D, et al. Profiling peripheral nerve macrophages reveals two macrophage subsets with distinct localization, transcriptome and response to injury. Nat Neurosci. 2020;23:676–89.PubMedPubMedCentralCrossRef
44.
45.
Neto E, Leitao L, Mateus JC, Sousa DM, Alves CJ, Aroso M, Monteiro AC, Conceicao F, Oreffo ROC, West J, et al. Osteoclast-derived extracellular vesicles are implicated in sensory neurons sprouting through the activation of epidermal growth factor signaling. Cell Biosci. 2022;12:127.PubMedPubMedCentralCrossRef
46.
Ito M, Muramatsu R, Kato Y, Sharma B, Uyeda A, Tanabe S, Fujimura H, Kidoya H, Takakura N, Kawahara Y, et al. Age-dependent decline in remyelination capacity is mediated by apelin-APJ signaling. Nat Aging. 2021;1:284–94.PubMedCrossRef
47.
Wang PL, Yim AKY, Kim KW, Avey D, Czepielewski RS, Colonna M, Milbrandt J, Randolph GJ. Peripheral nerve resident macrophages share tissue-specific programming and features of activated microglia. Nat Commun. 2020;11:2552.PubMedPubMedCentralCrossRef
48.
Shi GP, Sukhova GK, Kuzuya M, Ye Q, Du J, Zhang Y, Pan JH, Lu ML, Cheng XW, Iguchi A, et al. Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Circ Res. 2003;92:493–500.PubMedCrossRef
49.
Zhao P, Lieu T, Barlow N, Metcalf M, Veldhuis NA, Jensen DD, Kocan M, Sostegni S, Haerteis S, Baraznenok V, et al. Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4. J Biol Chem. 2014;289:27215–34.PubMedPubMedCentralCrossRef
50.
Akers IA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, McAnulty RJ. Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2. Am J Physiol Lung Cell Mol Physiol. 2000;278:L193-201.PubMedCrossRef
51.
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;83:175–85.PubMedCrossRef
52.
Boissonnas A, Louboutin F, Laviron M, Loyher PL, Reboussin E, Barthelemy S, Reaux-Le Goazigo A, Lobsiger CS, Combadiere B, Melik Parsadaniantz S, Combadiere C. Imaging resident and recruited macrophage contribution to Wallerian degeneration. J Exp Med 2020; 217.
53.
Sukhova GK, Zhang Y, Pan JH, Wada Y, Yamamoto T, Naito M, Kodama T, Tsimikas S, Witztum JL, Lu ML, et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;111:897–906.PubMedPubMedCentralCrossRef
54.
Sommerfeld SD, Cherry C, Schwab RM, Chung L, Maestas DR, Jr., Laffont P, Stein JE, Tam A, Ganguly S, Housseau F, et al. Interleukin-36gamma-producing macrophages drive IL-17-mediated fibrosis. Sci Immunol 2019; 4.
55.
Balce DR, Li B, Allan ER, Rybicka JM, Krohn RM, Yates RM. Alternative activation of macrophages by IL-4 enhances the proteolytic capacity of their phagosomes through synergistic mechanisms. Blood. 2011;118:4199–208.PubMedCrossRef
56.
Foy CA, Micheo WF, Kuffler DP. Functional recovery following repair of long nerve gaps in senior patient 2.6 years posttrauma. Plast Reconstr Surg Glob Open. 2021;9:e3831.PubMedPubMedCentralCrossRef
57.
Yang H, Dong Y, Wang Z, Lai J, Yao C, Zhou H, Alhaskawi A, Hasan Abdullah Ezzi S, Kota VG, Hasan Abdulla Hasan Abdulla M, Lu H. Traumatic neuromas of peripheral nerves: diagnosis, management and future perspectives. Front Neurol. 2022;13:1039529.PubMedCrossRef
58.
Foltan R, Klima K, Spackova J, Sedy J. Mechanism of traumatic neuroma development. Med Hypotheses. 2008;71:572–6.PubMedCrossRef
59.
60.
Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7:21–39.PubMedCrossRef
61.
Deshaies RJ. Multispecific drugs herald a new era of biopharmaceutical innovation. Nature. 2020;580:329–38.PubMedCrossRef
Metadata
Title
M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast–Schwann cell-signaling relay
Authors
Eri Oshima
Yoshinori Hayashi
Zhen Xie
Hitoshi Sato
Suzuro Hitomi
Ikuko Shibuta
Kentaro Urata
Junjun Ni
Koichi Iwata
Tatsuo Shirota
Masamichi Shinoda
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Nerve Injury
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02943-2

Other articles of this Issue 1/2023

Journal of Neuroinflammation 1/2023 Go to the issue

Research

Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome

Research

CSF-1R inhibitor PLX3397 attenuates peripheral and brain chronic GVHD and improves functional outcomes in mice

Research

Regulatory T cells decrease C3-positive reactive astrocytes in Alzheimer-like pathology

Research

Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aβ burden and restores memory functions in 5xFAD mice

Research

TSLP in DRG neurons causes the development of neuropathic pain through T cells

Research

Microglial aryl hydrocarbon receptor enhances phagocytic function via SYK and promotes remyelination in the cuprizone mouse model of demyelination