Disruption of the blood-nerve barrier contributes to pruritus

Xuzhou Central Hospital,Xuzhou 221006,China

【Abstract】Itchy substances originating from blood cells and associated nerve signaling are necessary for the happening of pruritus.The blood-nerve barrier (BNB) is a structure existing between blood vessels and nerve endings.Disruption of the BNB,which occurs in many pathological conditions,results in nerve inflammation and pain.Previous studies have demonstrated that BNB disruption and pruritus often coexist in the same diseases,such as diabetic neuropathy and chronic kidney disease.And cold pack therapy relieves pruritus while warm water exacerbates pruritus;pinching the calf or sitting cross-legged could relieve pruritus on feet and exerting substantial pressure on the itch site could relieve itch induced by the mosquito.According to the above references and facts,we hypothesize that disruption of the BNB is a critical step in the development of pruritus,and itchy substances and itch-associated nerve signaling are the basis of pruritus.This hypothesis emphasizes that the broken BNB is the most critical reason for pruritus rather than itchy substances or itch-associated nerve signaling,which can be used to explain the mechanism of pruritus in several pathological conditions and may lead to the development of new treatment in the clinic.

【Keywords】pruritus;itch;blood-nerve barrier;diabetes mellitus;chronic kidney disease;endothelial cells

Pruritus,commonly known as itch,is an unpleasant sensation of the skin that provokes a desire to scratch.While pruritus is a critical problem for many patients,its molecular mechanism remains unknown.Recent related studies have primarily focused on two facets.First,there is a desire to identify the substances that cause pruritus.Secondly,researchers are exploring the signaling pathways associated with pruritus in the central and peripheral nervous systems,including the specific receptors associated with itchy substances,secondary signaling messengers,and specific nerve signaling pathways[1-2].In the past decade,several itchy substances and their signaling pathways have been discovered.For example,the histaminergic pathway is known to involve the activation of phospholipase Cβ3 and phospholipase Aviabinding of histamine to H1 and H4 receptors.The binding induces the activation of the downstream target transient receptor potential V1.Next,itch signals are transferred to the central nervous system through mechanicallyinsensitive C-fibers,which can cause the itch sensation[3].Furthermore,some itchy substances commonly originate from specific blood cells,for example,histamine from leukocytes and mast cells,5-hydroxytryptamine from mast cells,and several interleukins from leukocytes[4].Although the studies mentioned above have provided some understanding of pruritis,many aspects of the pruritus remain unknown.

In patients with pruritus,the itch sensation requires the activation of specific receptors and its corresponding itchy substances.However,there are several components within the tissues that can limit the access of itchy substances to their receptors.Several components of the blood-nerve barrier (BNB) must be overcome for the substances to reach their associated receptors,which include endothelial cells,tight intercellular junctions,perineurial myofibroblasts,and connective tissues[5].Previously,abundant electron-dense intercellular tight junctions between the endothelial cells of the endoneurium,along with small (50-100 nm) intracellular pinocytic vesicles,have been detected in the vasculature surrounding the peripheral nerve[6].These observations indicate that the specialized interface between blood vessels and nerves displays barrier-like properties.However,the BNB is disrupted in many pathological conditions,such as inflammatory neuropathy[7],diabetic neuropathy[8],and neuropathic pain[9].Disruption of the BNB is often indicated by two pathological features,including paracellular leakage of harmful molecules into the surrounding nerve tissues and upregulation of adhesion molecules on the BNB structures,which allows for transcellular entry of hematogenous immune cells into the endoneurium where the cells initiate a local inflammatory cascade[8].

Hence,BNB disruption facilitates the development of certain pathological conditions[7-9],yet restoring the function of the BNB can improve symptoms such as pain[10].As pruritus shares familiar characteristics with nerve inflammation and pain,we are inspired to hypothesize that the BNB plays a critical role in pruritus.

1 The content of the hypothesis

In physiological conditions,the BNB prevents itchy substances from reaching the associated receptors on nerve endings.When the BNB becomes disrupted or weakened under certain pathological conditions,itchy substances would gain access to the nerve endings,leading to pruritus.

This hypothesis emphasizes the central role of BNB disruption in the development of pruritus rather than the increase of itchy substances or non-functional nerve signaling as described by the existing itch mechanism.In one condition,the level of itchy substances or functional itch-related nerve signaling may become faulty in some diseases,while pruritus would not present without the BNB disruption.In the other condition,BNB disruption could induce pruritus,even the levels of itchy substances and function of itch-associated nerve signaling keep normal.

2 Evaluation of the hypothesis

Currently,there is no direct evidence suggesting that disruption of the BNB is involved in the development of pruritus.However,a disrupted BNB or injured endothelial cells often co-exist in patients with pruritus,suggesting that there may be a connection between the disrupted BNB and pruritus.For example,diabetes disrupts the BNB and contributes to the formation of neuropathy with pain and itch[8].Excess glucose and increased fatty acid flux may damage the BNB due to the continuous exposure of endothelial cells to toxic substances circulating in the blood.In another study,disruption of the BNB was shown to directly contribute to neuropathic pain[10].Considering the similarities between itch and pain,it is possible to assume that BNB disruption may increase the intensity of diabeticinduced pruritus.A similar situation of BNB disruptioninduced pruritus may occur during the development of renal pruritus.In previous studies,endothelial cells were found to be susceptible to damage by uremic toxins,such as N(G),N(G)-dimethyl-L-arginine (ADMA),homocysteine,advanced glycation end products (AGEs),p-cresyl sulfate,and indoxyl sulfate.All of the toxins have similar mechanism of toxicity and are poorly removed by hemodialysis.In addition,they all promote pro-oxidant and pro-inflammatory responses,along with inhibiting the repair of endothelial cells.Also,uremic-associated pruritus is bothersome in most patients with end-stage renal disease.In summary,although the related evidence is limited,a close relationship between BNB disruption and pruritus may be present in some systemic diseases.

If this hypothesis is correct,substances that cause BNB disruption may be identified as itch-associated substances.Previously,the activation of the Wnt/β-catenin pathway in endothelial cells was found to cause BNB disruption through the downregulation of tight junction proteins in patients with neuropathic pain[9].Also,the tissue plasminogen activator (tPA) was shown to downregulate the expression of claudin-1 (tight junction protein) mRNA and protein by inducing the expression of miR-155-5p and miR-183-5p/3p[9,11].Therefore,the activation of the Wnt/β-catenin pathway in endothelial cells and tPA might facilitate the development of pruritus.Also,certain medications that can influence the integrity of the BNB might also influence the development and severity of pruritus.For example,hydrocortisone upregulates the expression of the tight junction protein,claudin-5[12],which may minimize the risk of pruritus.While,borneol can promote the translocation of claudin-5 into cells[13],which would result in the transient promotion of pruritus.Heparinase is another substance that may be able to induce pruritus.Accumulated evidence has suggested that lowdose low-molecular-weight heparin effectively treats lichen planus when accompanied by pruritus[14-15],which may be due to the inhibitory effects of heparinase on the BNB by low-molecular-weight heparin.

According to this hypothesis,the happening of pruritus requires three critical conditions,including blood perfusion containing itchy substances,disruption or weakening of the BNB,and functional nerve signaling pathways.Erasing each of the three conditions can prevent the development of pruritus,and some new therapies would then be developed.For examples,we previously attempted to relieve pruritus induced by tinea pedis by temporarily blocking local blood perfusion,such as pinching the calf or sitting cross-legged,and an acute itch caused by a mosquito by exerting substantial pressure on the itch site.Also,scratching,which relieves the itch by activating spinal interneurons and spinal thalamic tract neurons[16],might also be explained by this theory,that is,scratching relieves the itch by transiently reducing the local blood perfusion.As additional evidence of the connection between blood perfusion and pruritus,cold stimulation can inhibit histamine-induced itch,and cold pack therapy is an effective treatment for burn-scar pruritus[17],While hot water and warm temperatures were found to exacerbate the itchiness[18].Moreover,this hypothesis might help to identify several new molecular targets for the treatment of pruritus.The integrity of the BNB depends on the expression of the hedgehog signaling pathway,which is responsible for maintaining the function of tight junctions[19].In patients with neuropathic pain or diabetic neuropathy,the activation of hedgehog signaling pathways was found to be disrupted[10].Hence,drugs that restore the hedgehog pathway in endothelial cells may effectively treat pruritus.Finally,excellent nutrition and daily skincare may help prevent the development of pruritus caused by certain pathological situations,as these measures can improve the integrity of the BNB[20].

3 Consequences of the hypothesis and discussion

In this hypothesis,broken or weaken BNB is critical for pruritus,while itchy substances originated from blood and functional nerve signaling are the basis of pruritus.Broken BNB is involved in pain.Considering pruritus is a familiar process with pain,the content of this hypothesis is reasonable.Also,this hypothesis is supported by several indirect evidence for now.First,pruritus and broken or weaken BNB always co-exist in the same pathological condition,such as diabetes[8],end-stage renal disease[21]and burn[22];second,cold pack therapy could relieve pain[17],while warm water could exacerbate the itchiness[18].The reason is that cold or warm media affect the blood perfusion as well as the number of itchy substances in the blood;third,from personal experience,pinching the calf or sitting cross-legged could relieve pruritus reduced by tinea pedis and exerting substantial pressure on the itching skin could relieve itchy induced by a mosquito.The above measures may also alleviate pruritus by reducing blood perfusion and itchy substances.Without confidential evidence is a shortcoming of the present hypothesis,but it also indicates the perceptiveness of this hypothesis to some degree.

This hypothesis may change the direction of future research in the field,as well as benefit the development of new therapies for pruritus.Specific itchy substances and the associated nerve signaling are necessary for the development of pruritus.However,without disruption of the BNB,itchy substances would be unable to reach and activate the receptors on the nerves to induce pruritus.Hence,BNB disruption may be the most critical element of pruritus.This hypothesis supplies an important part that was missing from the current explanation of pruritus.

To effectively treat pruritus,further investigations of BNB disruption and its role in pruritus may be a research direction.The identification of specific itchy substances is also a research direction.However,for nearly all itchy substances are not specific to pruritus,reducing itchy substances may influence other physiological or pathological conditions.Another research direction is the study of nerve signaling induced by itchy substances.But the inhibition of nerve signaling is only a temporary solution,as the itch would relapse once the nerve signaling inhibitor is gone.In summary,restoring the integrity of the BNB may be the best strategy to treat pruritus,as it is the only one which addresses the primary cause of pruritus.