The Role Of Acid-sensing Ion Channel 3 In Chronic Inflammation

Acid-sensing ion channels(ASICs)are proton-gated cation channels.They are widely expressed in neurons throughout the central and peripheral nervous systems and commonly known to play significant roles in a variety of neurological functions.In addition to neurons,some ASIC isoforms have also been shown to express in peripheral non-neuronal tissues,such as immune cells,where its role remains unclear.Considering the acidic nature of airway vapor condensate in allergic diseases,such as allergic rhinitis(AR),asthma,and allergic dermatitis,we examined the contribution of ASIC3,a major ASIC subunit detected in dendritic cells,in allergic diseases and chronic inflammation.Using an ovalbumin-induced allergic rhinitis(AR)mouse model,we found that genetic deletion of Asic3 significantly ameliorated both the behaviorally-characterized sneezing symptoms and the pathologic changes of nasal mucosa.In accordance with these changes,the cytokines interleukin-4 and 5,produced by type 2 helper T(Th2)cells,were significantly increased in the AR model of WT but not Asic3 null mice.On the other hand,while Th1-derived interferon-?,a cytokine known to inhibit Th2-mediated immune responses,was not affected in the AR model of WT mice,it was aberrantly increased in that of Asic3 null mice,demonstrating a dysregulated immune response in the absence of Asic3.Further study confirmed that Asic3 was expressed in BMDC and extracellular acidosis upregulated the expression of CD80,MHC II and CD86 of BMDC via ASIC3.Taken together,our work identifies a novel pathological role of ASIC3 in allergic rhinitis and suggests that this channel may be a new therapeutic target for treatment of allergic diseases.To further expand the functional significance of ASIC involvement in chronic inflammation processes,we further studied the roles of ASIC3,an ASIC subunit richly expressed in peripheral sensory neurons,in skin inflammation-related chronic itch.In a dry skin pruritus model,we found that ASIC3-deficient animals displayed substantially less scratching behavior and reduced pathological skin changes.Interestingly,under the dry skin chronic itch model,ASIC3 plays an essential role in itch response and epidermal hyperplasia in scratchable surface areas,but not the non-scratchable area,indicating that scratching of the affected skin area is essential for the ASIC3-depenedent phenotypes.This probably reflects the need for inflammation(and the accompanied tissue acidosis),an inevitable consequence of scratching the damaged skin,to induce ASIC3 activity.Thus,our study identifies a novel ASIC3-mediated neuroimmune interaction mechanism that contributes to the skin inflammation associated with chronic itch.To further understand the molecular and cellular mechanisms underlying the roles of ASIC3 in chronic itch,we performed itch test by repetitively exposing mice to pruritogens to induce itch tachyphylaxis,which could be substantially reversed by the simultaneous presence of acidosis.Importantly,acidosis-mediated abolishment on tachyphylaxis to successive pruritogenic itch depends on ASIC3.Moreover,ASIC3-mediated itch de-desensitization largely relied on the enhanced activation of MrgprC11-mediated pruritogen-responsive sensory neurons.Together,our study demonstrates a critical role of ASIC3 in chronic itch and suggests a novel itch transduction mechanism.As chronic itch that is insensitive to antihistamine treatment is a major manifestation of multiple skin and systematic diseases,ASIC3 may be an ideal therapeutic target of itch and pain associated with skin and systematic diseases.