Bone marrow-derived TNF-α causes diabetic neuropathy in mice

Abstract

Aims/hypothesis Dysregulation of biochemical pathways in response to hyperglycaemia in cells intrinsic to the nervous system (Schwann cells, neurons, vasa nervorum) are thought to underlie diabetic peripheral neuropathy (DPN). TNF-α is a known aetiological factor; Tnf-knockout mice are protected against DPN. We hypothesised that TNF-α produced by a small but specific bone marrow (BM) subpopulation marked by proinsulin production (proinsulin-producing BM-derived cells, PI-BMDCs) is essential for DPN development. Methods We produced mice deficient in TNF-α, globally in BM and selectively in PI-BMDCs only, by gene targeting and BM transplantation, and induced diabetes by streptozotocin. Motor and sensory nerve conduction velocities were used to gauge nerve dysfunction. Immunocytochemistry, fluorescence in situ hybridisation (FISH) and PCR analysis of dorsal root ganglia (DRG) were employed to monitor outcome. Results We found that loss of TNF-α in BM only protected mice from DPN. We developed a strategy to delete TNF-α specifically in PI-BMDCs, and found that PI-BMDC-specific Conclusions/interpretation BMDC-specific TNF-α is essential for DPN development; its selective removal from a small PI-BMDC subpopulation protects against DPN. The pathogenicity of PI-BMDC-derived TNF-α may have important therapeutic implications.

Ablation of a small subpopulation of diabetes-specific bone marrow-derived cells in mice protects against diabetic neuropathy

“…Before diabetes induction, none of the mouse DRGs displayed detectable PI or TNF␣ immunostaining. In agreement with previous observations (8,18,22,27), we noted a large number of immunoreactive PI-positive and TNF␣-positive cells in the DRGs of the diabetic (DM) iDTRf¡WT control mice. Importantly, we found a significantly reduced number of PI-and TNF␣-positive cells in the DRGs of DM DT-ablated iDTR-f/RIP-Cre¡WT mice (Fig.…”

“…In contrast, however, the mRNA expression level of these mRNAs was not significantly different in the DRGs of non-DM or DM iDTR-f/RIP-Cre¡WT mice. Therefore, DT ablation of PI-BMDCs substantially reduced the level of PIBMDCs (marked biochemically by Ins1 and Ins2 expression) in the DRGs of iDTR-f/RIP-Cre¡WT mice; ablation also substantially suppressed the level of Tnf mRNA expression, a gene product known to occur in PI-BMDCs that had also been shown to play a pathogenic role in DPN (8,18,22,27).…”

“…We recently showed strong evidence for an essential role of TNF␣ in mediating the ill effects of PI-BMDCs (8,18,22,27). of nuclei in DRG before (non-DM) and 12 wk after STZ administration (DM) in iDTRf¡WT (n ϭ 5, n ϭ 10) or iDTR-f/RIPCre¡WT (n ϭ 6, n ϭ 7) mice.…”

“…We subsequently reported that the diabetes-specific PI-BMDCs play a key role in the pathogenesis of DPN by directly damaging dorsal root ganglion (DRG) neurons in diabetic rodents (19). Most of these abnormal PIBMDCs coexpress TNF-␣; the TNF␣-expressing PI-BMDCs fuse with DRG neurons, leading to their malfunction and premature apoptosis, culminating in DPN (8,18,22,27).Studies to date strongly suggest that PI-BMDCs are heavily involved in the pathogenesis of DPN. In this investigation, we sought to determine whether PI-BMDCs play an essential role in DPN development and whether this cell type could be a target for therapeutic intervention.…”

“…We subsequently reported that the diabetes-specific PI-BMDCs play a key role in the pathogenesis of DPN by directly damaging dorsal root ganglion (DRG) neurons in diabetic rodents (19). Most of these abnormal PIBMDCs coexpress TNF-␣; the TNF␣-expressing PI-BMDCs fuse with DRG neurons, leading to their malfunction and premature apoptosis, culminating in DPN (8,18,22,27).…”