Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats

Abstract

The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68+ macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy.

Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy

“…We then hypothesized that changes could be more selective in particular DRG areas. Therefore, we used LMD in order to separately analyze expression levels of corresponding barrier proteins in the DRG neuron-rich and fiber-rich region [15]. However, Cldn1 and Tjp1 expression levels in the neuron-rich region and Cldn5 in capillaries were unchanged 8 weeks after STZ (Fig.…”

“…They recapture molecules leaking through the BNB as there is increased transcytosis in the BNB in comparison to the BBB. Increased barrier permeability like in traumatic nerve injury [14,15] not only facilitates potentially harmful molecule diffusion into the nerve but also supports immune cell transcellular migration by adhesion molecule upregulation [4]. Tight junction protein downregulation, e.g., Cldn1 or Tjp1 [9][10][11][12], and junctional adhesion molecules (JAM) or intercellular adhesion molecule upregulation can both contribute to BNB dysfunction [4,16].…”

Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination

“…A series of von Frey filaments (Aesthesio set, Ugo Basile) were used to record the withdrawal threshold of the hind paw to identify the mechanical allodynia response (Lux et al, 2019) and touch sensitivity in neuropathy. Filaments were applied to the plantar surface of the hind paw and held for 1-3 s, until they were bent to a 45° angle.…”

Special Issue on “The Tight Junction and Its Proteins: More than Just a Barrier”

“…The blood–DRG barrier (BDB) properties in these physiologically distinct regions are altered after nerve injury by changes in specific spatial TJ protein expression. For example, in the neuron-rich regions, claudin-5 was specifically downregulated, leading to the higher permeability of this barrier, while the other regions were not affected [ 32 ].…”