Lysosomal capacity, not phagocytic appetite, gates myelin debris clearance in the injured peripheral nerve

Question: How do macrophage lysosomal adaptation programs, such as TFEB/TFE3 activation and lysosomal gene expression remodeling, regulate the clearance of myelin debris after peripheral nerve injury?

Answer

Taken together, the retrieved papers support a two-part position. First, the rate-limiting step in myelin debris clearance after peripheral nerve injury is lysosomal degradation capacity rather than particle uptake: the one genetic study that directly dissects this step shows that losing a single lysosome-regulating protein (GPNMB) leaves injured nerves with persistent myelin debris and impaired functional recovery while macrophages remain present and phagocytically engaged [6]. Second, the mechanistic attribution to TFEB/TFE3 specifically is inferential rather than demonstrated in nerve macrophages—no retrieved paper deletes, activates, or measures TFEB/TFE3 in macrophages of an injured peripheral nerve. The strongest evidence that TFEB-driven lysosomal remodeling expands degradative capacity under lipid cargo load comes from hepatic tissue macrophages, where inducible TFEB protects Kupffer cells from lipid-stress death via lysosomal lipolysis and mitochondrial fatty-acid oxidation [16]. Across these papers, the defensible synthesis is that lysosomal adaptation is a required, macrophage-intrinsic, transcriptionally plastic determinant of debris clearance, that GPNMB is its currently validated PNS node, and that TFEB is a plausible but untested upstream regulator whose activation is cell-type-context-dependent and, in myelin-producing cells, inhibitory.

Clearance fails at the degradation step, not at the engulfment step

Loss of Gpnmb in mice impaired functional recovery after sciatic nerve crush and produced persistent myelin debris accumulation with defective debris clearance and impaired macrophage lysosomal function within injured nerves [6]. In that study the defect was localized to processing rather than recognition: GPNMB-deficient human iPSC-derived macrophages showed impaired lysosomal adaptation, reduced lysosomal fitness, and defective processing of myelin-associated cargo, resulting in inefficient degradation of injury-associated material [6]. This division of labour is corroborated in macrophages generally: without an activating ligand, fewer than half of phagosomes fuse with lysosomes, and p38α MAPK signalling is required to enhance cargo delivery to lysosomes and acidification [20]. Uptake and digestion are also dissociable in the opposite direction—Stx2 depletion increases particle uptake while preventing phagosome–lysosome fusion and impairing digestion [19]—and macrophages at maximal phagocytic capacity lose appetite because their free endosome and lysosome pools are depleted, a state reversed if phagosome resolution is permitted [17]. Lysosomal biogenesis is therefore predicted to set the ceiling on sustained clearance, not merely to accelerate it.

TFEB activation improves macrophage fitness under lipid load, which is the closest available model of myelin cargo

Induced TFEB expression in Kupffer cells protected them from death in two mouse models of metabolic liver disease, reduced steatosis through a mechanism dependent on macrophage lysosomal lipolysis and mitochondrial fatty acid oxidation, and reduced ferroptotic and oxidative death via enhanced NADPH [16]. That study frames TFEB as protecting macrophages from lipid stress, a role the authors note has also been shown in atherosclerosis [16]. The upstream logic connecting cargo overload to TFEB is also supported: lysosomal membrane damage recruits MTMR14, whose local phosphoinositide remodelling reduces mTORC1 signalling and global protein synthesis as an acute proteostatic adaptation, and loss of MTMR14 increases sensitivity to lysosomal injury [23]; lysosomal damage likewise recruits VPS13C to deliver ER-derived lipid for membrane repair [10]. TFEB activation downstream of lysosomal calcium release through MCOLN1 has been shown directly in infected macrophages [15], establishing the sensor-to-transcription axis in the relevant cell type, though not in the context of myelin phagocytosis.

TFEB activity is not uniformly pro-reparative, and in myelin-forming cells it restrains myelin

In zebrafish, loss of Tfeb restored deficient myelination in tmem106b double mutants, and the authors state explicitly that TFEB inhibits myelination [1]. This establishes that the TFEB pathway is a modulator of white matter biology whose direction of effect depends on which cell in the lesion is being considered, and it argues against systemic TFEB agonism as a repair strategy: the same transcriptional program invoked to raise macrophage degradative capacity acts on oligodendrocytes to suppress myelin production [1].

What counts as "lysosomal adaptation" is broader than gene expression, and GPNMB sits inside it

GPNMB is secreted by macrophages in response to lysosomal stress via lysosomal exocytosis, is modulated by LRRK2, and behaves as a biomarker of lysosomal dysfunction [12]. Read against the nerve injury data, this makes GPNMB both a readout of lysosomal stress and a functional requirement for lysosomal fitness [6][12]. Adaptation also includes membrane repair, and repair repertoires differ by cell type: astrocytes preferentially recruit ESCRT machinery and activate TBC1D15-dependent lysosomal membrane reformation more robustly than neurons, while the PITT lipid-transfer pathway is engaged in both [11]. Lysosomal stress can additionally reroute cargo handling away from cell-autonomous degradation altogether, driving cell-surface tmCSF1 expression and macrophage trogocytosis of the offending material [3].

Cargo recognition and non-macrophage phagocytes bound what lysosomal capacity can deliver

Axonal debris from injured nerves carries elevated CASPR, is phagocytosed more efficiently than debris from healthy nerves, and uptake is strongly reduced by CASPR function-blocking antibodies, identifying an eat-me signal that sets uptake efficiency independently of degradation [7]. Schwann cells are a parallel phagocyte population: erythropoietin enhanced repair Schwann cell phagocytosis of myelin debris at crush sites and improved the sciatic functional index [5]. Macrophage-intrinsic programs other than lysosomal gene remodeling also gate clearance—Sarm1-null macrophages show difficulty phagocytosing and clearing myelin debris, recapitulated with a macrophage-specific knockout that delays regeneration [8].

Where lysosome-dependent myelin processing becomes pathogenic

In the CNS, perivascular cells take up myelin debris via Axl and degrade it through LC3-associated phagocytosis, and myelin phagocytosis drives their proliferation, fibrosis and lesion progression rather than repair [4]. Aged microglia show reduced clearance of dead myelin with lipid droplet accumulation and impaired remyelination, and microglial renewal restores demyelination–remyelination capacity [2]. The chemistry of the cargo explains why capacity matters: myelin-derived cholesterol is processed through late endosomes and lysosomes, with lysosomal acidification required for crystal dissolution and lysosomal sterol export blockade causing retention [22], and lysosomal acid lipase supplies free cholesterol needed for lipid raft assembly during phagosomal maturation [21].

Conflicts and gaps

The central disagreement is directional. The GPNMB loss-of-function data place lysosomal failure upstream of debris persistence [6], whereas the aging data place cargo overload and lipid accumulation upstream of microglial exhaustion [2]; no retrieved paper resolves whether myelin cargo causes the lysosomal lesion or reveals it. A second conflict concerns valence: lysosomal myelin processing is presented as required for PNS functional recovery [6] but as a driver of fibrosis and lesion progression in CNS perivascular cells [4]. Third, TFEB/TFE3 is never measured in injured-nerve macrophages; the only PNS TFEB data retrieved concern neurons, where paclitaxel drives nuclear TFEB upregulation and LAMP1 induction in DRG neurons [18]. Whether GPNMB is a TFEB target, a TFEB co-factor, or an upstream regulator of TFEB is unresolved—its stress-induced secretion via lysosomal exocytosis suggests a downstream readout, yet its loss produces an adaptation failure [12][6]. Finally, no retrieved study quantifies the relative contributions of macrophages and Schwann cells to debris clearance in the same nerve, despite both being documented as competent phagocytes [6][5][7].

What would change the answer

A macrophage-specific, tamoxifen-inducible Tfeb/Tfe3 double knockout combined with a constitutively active (S211A/S142A) knock-in, both crossed into the sciatic nerve crush model, would directly test whether TFEB/TFE3 is required and sufficient for debris clearance and functional recovery. The readout should be lysosome-resolved rather than bulk: lysosomal immunoprecipitation lipidomics of sorted nerve macrophages, as applied to define GBA1 substrate accumulation [13] and BMP turnover [14], would reveal whether myelin-derived cholesterol, sulfatide and plasmalogen species accumulate or clear, and longitudinal MRI of the injured nerve as used for Gpnmb phenotyping would give non-invasive clearance kinetics [6]. Cargo-side specificity could be isolated with pH-sensitive or photoconvertible myelin probes and by blocking the degradation arm directly—lysosomal acid lipase inhibition [21] or NPC1/U18666A sterol export blockade [22]—in macrophage–myelin co-cultures. To establish the GPNMB–TFEB relationship, CUT&RUN and ATAC-seq for TFEB in GPNMB-sufficient versus GPNMB-deficient iPSC macrophages, plus rescue of Gpnmb loss by TFEB agonism, would be decisive. Cell-type-resolved translatome profiling from injured nerve, analogous to RiboTag work in axotomized motoneurons [9], would finally identify the endogenous lysosomal gene program of nerve macrophages in vivo rather than inferring it from liver or CNS macrophages.

References

[1] Berdowski, W., van der Linde, H. C., Wolf, N. I., van Ham, T. J.. "TFEB-depletion rescues TMEM106B-related myelin defects in zebrafish". bioRxiv. 2025-10-11T00:00:00.000Z. URL: https://doi.org/10.1101/2025.10.10.681547

[2] Boutou, A., Roufagalas, I., Papazian, I., Abbadessa, G., Asprou, K., Howell, O. W., Kourouvani, M., Sainouchi, M., Farkas, I., Pogka, V., Tremoulis, D., Karamitros, T., Lassmann, H., Nicholas, R., Bauer, J., Probert, L.. "Age-related loss of brain demyelinating and remyelinating potential is overcome by microglia renewal". bioRxiv. 2026-06-18T00:00:00.000Z. URL: https://doi.org/10.64898/2026.06.15.732390

[3] Kimura, Y., Sato, K., Chavan, A. R., Kasberg, W., Silva, M., Qiu, W., Iyer, N., Innerberger, M., Siwanowicz, I., Pope, S. D., Rangavajhula, A., Yao, G.-Q., Insogna, K., Trautman, E. T., Bleck, C. K., su, x., Lippincott-Schwartz, J., Medzhitov, R.. "Non-cell-autonomous removal of protein aggregates via trogocytosis". bioRxiv. 2026-10-19T00:00:00.000Z. URL: https://doi.org/10.64898/2026.10.13.758691

[4] Zhou, T., Zhang, Z., Zeng, F., Song, H., Xu, Z., Hu, Z., Yao, L., Wang, W., Zhang, T., Du, X., Li, K., Xie, Z., Sun, Y., Ren, B., Fan, B., Qi, S., Li, Y., Hu, Y., Huang, M., Chen, Y., Wang, Q., Zhao, N., Ayazi, M., Yu, S., Hu, N., Sun, H., Sui, L., Huang, K., Qu, Q., Liu, Q., Pfrieger, F. W., Cao, X., Zhang, C.-S., Mao, K., Wang, B., Jie, Z., Bu, G., Mei, F., Megraw, T., Wang, L., Ren, Y., Zheng, Y.. "Phagocytic activity of perivascular cell promotes CNS injury pathology". bioRxiv. 2026-08-09T00:00:00.000Z. URL: https://doi.org/10.64898/2026.08.03.742479

[5] Govindappa, P. K., Ellur, G., Hegarty, J. P., Gupta, A., VG, R., Elfar, J. C.. "Erythropoietin decreases apoptosis and promotes Schwann cell repair and phagocytosis following nerve crush injury in mice". bioRxiv. 2025-01-23T00:00:00.000Z. URL: https://doi.org/10.1101/2025.01.22.634402

[6] Ouali Alami, N., Panesar, M., Obrecht, M., Doll, T., Osinnii, I., Sansig, G., Thiel, Z., Claerr, I., Greenwood, D., Patino, C., Klein, L., Condeescu-Ivan, D., Giorgetti, E., Lambert, C., Kalamakis, G., Van Steenbergen, V., Hils, L., Manneville, C., Mueller, M., Nash, M., Labouesse, M., Shimshek, D., Beckmann, N., Dergai, O., Bidinosti, M.. "GPNMB enables lysosomal adaptation required for myelin clearance and nerve regeneration after peripheral nerve injury". bioRxiv. 2026-10-19T00:00:00.000Z. URL: https://doi.org/10.64898/2026.10.12.758439

[7] Meyer zu Reckendorf, S., Klein, A. L., Seitz, A., Hegler, J., Klugmann, C., Sinske, D., Deininger, S., Pedro, M. T., Knoell, B.. "CASPR facilitates clearance of degenerating axons by Schwann cells and macrophages after peripheral nerve injury". bioRxiv. 2025-10-20T00:00:00.000Z. URL: https://doi.org/10.1101/2025.10.19.683281

[8] Bennett, J., Adesunkanmi, H., Leever, N., Bergeron, G., Small, J., Holladay, C., Saxman, G., Williamson, R. E., Swain, M., Pearson, G., Patel, M., Kalinski, A. L.. "SARM1 is required for macrophage immunophenotype switching that is essential for nerve repair". bioRxiv. 2026-04-09T00:00:00.000Z. URL: https://doi.org/10.64898/2026.04.07.716973

[9] Molina, B., Pujol-Masip, M., Ovelleiro, D., Gomez-Sanchez, J. A., Lago, N., Udina, E.. "Assessment of Motoneuronal Regeneration and Wallerian Degeneration Following Axotomy in Postnatal Mice". bioRxiv. 2025-12-14T00:00:00.000Z. URL: https://doi.org/10.64898/2025.12.03.691768

[10] Adeosun, O. A., Schroer, C., Suedhoff, E., Bergenthal, F., Sommer, K., Doeffinger, E., Fiedler, B., Hilderink, A., Lehmann, A.-K., Pohle, L.-S., Froehlich, F., Maeda, K., Kurre, R., Holtmannspoetter, M., Esch, B. M., Holthuis, J. C. M.. "VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair". bioRxiv. 2025-10-24T00:00:00.000Z. URL: https://doi.org/10.1101/2025.10.23.684214

[11] Smith, E. M., Chanaday, N. L., Maday, S.. "Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons". bioRxiv. 2025-09-08T00:00:00.000Z. URL: https://doi.org/10.1101/2025.09.07.674666

[12] Bogacki, E. C., Longmore, G., Lewis, P. A., Herbst, S.. "GPNMB is a biomarker for lysosomal dysfunction and is secreted via LRRK2-modulated lysosomal exocytosis". bioRxiv. 2025-01-01T00:00:00.000Z. URL: https://doi.org/10.1101/2025.01.01.630988

[13] Lin, C., Iguchi, M., Oh, J., Levina, A., Zhu, Z., Xiong, J., Dong, W., Alsohybe, H. N., Briceno, N., Chau, K., Isakova, A., Chen, Y., Sidransky, E., Abu-Remaileh, M.. "Lysosomal lipidomics identifies glycosylated bis(monoacylglycero)phosphate as a novel biomarker of mutant GBA1". bioRxiv. 2026-10-15T00:00:00.000Z. URL: https://doi.org/10.64898/2026.10.13.758908

[14] Nyame, K., Xiong, J., de Jong, A., Alsohybe, H. N., Raaben, M., Hartmann, G., Simcox, J. A., Blomen, V., Abu-Remaileh, M., Pena, I. V., de Miguel, R., Brummelkamp, T. R., Nijman, S. M. B.. "PLA2G15 is a Lysosomal BMP Hydrolase and Its Targeting Ameliorates Lysosomal Disease". bioRxiv. 2025-02-20T00:00:00.000Z. URL: https://doi.org/10.1101/2024.06.07.597919

[15] Rinkel, S., Schulze-Luehrmann, J., Weber, F., Liebler-Tenorio, E., Luehrmann, A.. "TFEB and MCOLN1 are important for Coxiella burnetii egress via lysosomal exocytosis". bioRxiv. 2026-05-08T00:00:00.000Z. URL: https://doi.org/10.64898/2026.05.07.723496

[16] Chan, M. M., Daemen, S., Beatty, W., Byrnes, K., Cho, K., Ferguson, D., Park, A. C., Fu, C. F., Guo, Z., Feldstein, N., Park, C., Florczak, K. L., He, L., Yang, B. Q., Javaheri, A., Patti, G., Finck, B., Razani, B., Schilling, J. D.. "Induction of TFEB promotes Kupffer cell survival and reduces lipid accumulation and inflammation in MASLD". bioRxiv. 2025-04-24T00:00:00.000Z. URL: https://doi.org/10.1101/2025.04.19.649650

[17] Fountain, A., Mansat, M., Lackraj, T., Gimenez, M. C., Moussaoui, S., Ezzo, M., Soffiaturo, S., Urdaneta, E., Verdawala, M. B., Fung, K., Lancaster, C., Somerville, E., Hinz, B., Terebiznik, M., Botelho, R. J.. "Depletion of endomembrane reservoirs drives phagocytic appetite exhaustion in macrophages". bioRxiv. 2025-07-10T00:00:00.000Z. URL: https://doi.org/10.1101/2024.07.31.605905

[18] Domalogdog, K. C., Sankaranarayanan, I., Franco-Enzastiga, U., Mwirigi, J. M., Nguyen, S. M., Tavares-Ferreira, D. J., Price, T. J.. "Live cell imaging reveals paclitaxel-induced lysosome motility and function disruption in DRG neurons". bioRxiv. 2026-05-21T00:00:00.000Z. URL: https://doi.org/10.64898/2026.05.19.726221

[19] Samanta, S., Nandi, A., Datta, R., Dolai, S.. "Syntaxin-2 coordinates endolysosomal trafficking to balance phagocytic uptake and phagolysosomal clearance in macrophages". bioRxiv. 2024-12-11T00:00:00.000Z. URL: https://doi.org/10.1101/2024.06.08.598083

[20] Shah, M., Kirthivasan, N., Chakraborty, S., Krishnan, Y., Jhunjhunwala, S.. "Phagosome Maturation in Macrophages is Enhanced by p38α MAPK Signaling". bioRxiv. 2025-07-06T00:00:00.000Z. URL: https://doi.org/10.1101/2025.07.03.662985

[21] Saharan, O., Bhawna, B., Saraswati, S. S. K., Akhir, A., Chopra, S., Kumar, D., Mallik, R., Kamat, S.. "Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation". bioRxiv. 2026-09-22T00:00:00.000Z. URL: https://doi.org/10.64898/2026.09.18.752819

[22] Akkerman, V., Juhl, A. D., Egebjerg, J. M., Pratsch, C., Werner, S., Schneider, G., Willms, T., Müller, P., Kapishnikov, S., Wüstner, D.. "Multimodal 3D imaging reveals a central role for lysosomes indissolution of cholesterol crystals by macrophages". bioRxiv. 2026-09-23T00:00:00.000Z. URL: https://doi.org/10.64898/2026.09.22.753145

[23] Su, Y., Mello-Vieira, J., Puchkov, D. P., Dornan, G. D., Ruwolt, M., Suedhoff, E., Adeosun, O. A., Vogel, H., Suendermann, S., Schuermann, A., Holthuis, J., Liu, F., Dikic, I., Ebner, M., Haucke, V.. "Damage sensing recruitment of a lipid phosphatase couples lysosomal membrane repair to proteostatic adaptation". bioRxiv. 2026-04-05T00:00:00.000Z. URL: https://doi.org/10.64898/2026.04.04.716461

How this survey was made

This survey answers one question: “How do macrophage lysosomal adaptation programs, such as TFEB/TFE3 activation and lysosomal gene expression remodeling, regulate the clearance of myelin debris after peripheral nerve injury?”

We keep our own collection of recent preprints and refresh it every day from bioRxiv, medRxiv, arXiv, PsyArXiv, SocArXiv and ChemRxiv. For each survey, we search that collection for recent work and keep the strongest matches: papers that use the same terms as the question, and papers on the same topic in different words.

The text was written from the titles and abstracts of those papers; the full texts were not read. Statements that draw on a particular paper are marked with a number in brackets. The reference list just above is the 23 papers whose work this text draws on, chosen from the 150 papers those searches returned; the rest of the shortlist is not printed. It is not a complete review of everything published on the question.

Treat this as a starting point and a reading list, not a peer-reviewed review. The searches behind this survey ran on October 21, 2026 and covered work from the previous two years.