Inflammation and macrophages once again: the role of MANF in diabetic peripheral neuropathy

Aims: To investigate, in mice models, the role of Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) in diabetic peripheral neuropathy (DPN) progression and its potential role as therapeutic target.

Methods: At baseline (D0) two groups were established: DPN diabetic group, in which mice received a single intraperitoneal injection of streptozotocin (dosage of 100 mg/kg), and a control group, in which mice received only vehicle injections. At D7, each group was divided in two subgroups: two of these received 5 μg rhMANF injection from D7 to D21 (the Control+rhMANF group and DPN+rhMANF group) and the other two received saline injections from D7 to D21 (the Control+Saline group and the DPN+Saline group). Measurements for blood glucose levels, body weight, and Paw Mechanical Withdrawal Threshold (PMWT) were taken every 7 days. On D42, Glycated Hemoglobin (HbA1c) assessment, electromyography, Western blot [tissue samples from L4-L6 dorsal root ganglia (DRG) and sciatic nerves] and immunofluorescence assay (tissue samples from L4-L6 range of the lumbar DRG, sciatic nerve, and plantar skin from mice) were performed.

Results: In the DPN group, when compared to controls, there was a significant upregulation of MANF protein levels in the DRG (p<0.0001) and sciatic nerve (p<0.01), due to an increased presence of MANF-expressing macrophages, and a pronounced decrease in PMWT. Then, intravenous administration of recombinant human (rh) MANF from D7 to D21 post-STZ injection carried on multiple beneficial outcomes in DPN+rhMANF group compared to DPN+Saline group: rhMANF treatment improved PMWT results (p=0.0428 on D42), enhanced sciatic nerve conduction (p=0.007), increased intradermal nerve density (more PGP9.5-positive nerve fibers in the plantar skin, p=0.0015). These improvements were associated with reduced CD68+/Iba-1 macrophage and an increase of MANF+/Iba-1+ macrophages (p<0.05) infiltration in the DRG and sciatic nerve, and inhibition of inflammatory signaling pathways [decreased NF-κB p65 phosphorylation (p=0.0004) and suppressed p38 MAPK phosphorylation (p=0.007)]. No significant differences were found between the Control+Saline and Control+rhMANF groups or in the glycemic control between DPN+rhMANF group compared to DPN+Saline group.

Conclusions: MANF is a potential therapeutic target for DPN, particularly due to its anti-inflammatory properties.

Comments: In this complex and interesting study, once again the authors enlightened how immunoinflammatory responses play a significant role in DPN progression. Among them, a key inflammatory mechanism involves the infiltration and activation of macrophages within the peripheral nervous system. MANF is a neuroprotective protein, expressed by neurons and in microglia/macrophages, triggered under endoplasmic reticulum stress, and able to inhibit the NF-κB inflammatory signalling pathway and modulate immuno-inflammation through a balance between pro-inflammatory M1 type and tissue repair promoting M2 type macrophages. The supplementation of rhMANF was shown to reduce neuron damage in animal models of Alzheimer's disease and cerebrovascular events (Xu S et al J Neuroinflammation. 2019;16:35; Zhao X et al Int Immunopharmacol. 2024;127:111396).

This study suggests that also in DPN, rhMANF treatment could play a role in promoting the count of MANF-expressing macrophages in the DRG thus preserving (and partially recovering) nerve fibre damage, beyond the glycaemic control.  Further studies are required to corroborate these findings.

Marika Menduni

Reference: Dai P, Wang P, Chen X, Feng S, Wu F, Zheng X, Qin Z. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Restricts Inflammatory Progression through Limiting Macrophage Infiltration in DRG and Sciatic Nerve during Diabetic Peripheral Neuropathy. ACS Chem Neurosci. 2025 Mar 5;16(5):945-959. doi: 10.1021/acschemneuro.5c00021. Epub 2025 Feb 19. PMID: 39970444.

🔗 https://pubs.acs.org/doi/10.1021/acschemneuro.5c00021