Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite ...this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either
or
, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not
animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.
Itch is a sensation in the skin which provokes the desire to scratch. In the past few decades there has been a significant elucidation of the immune and neural pathways which underly the sensation of ...itch. An interesting divergence in the itch pathway relates to the type of stimulation used to evoke an itchy sensation. Commonly, chemical mediators of itch such as histamine are injected into the skin where they activate their cognate receptors on sensory neurons. Another way to evoke itch, particularly in patients with chronic itch, is to use light mechanical stimulation. Investigation into these pathways utilizing the mouse model have shown that the neuronal pathways which underly chemical itch are distinct from those which mediate itch in response to mechanical stimulation. Specific populations of primary sensory neurons, spinal interneurons and transmission neurons have been identified which suggests a labeled line for itch transmission. Additionally, Piezo channels, which underly mechanosensation, were discovered to play an important role in the mechanical itch pathway. Given these novel findings relating to the mechanical itch pathway, the purpose of this review is to summarize the reports from human subjects and animal studies to highlight the advances in our understanding of mechanical itch and alloknesis.
Chronic itch accompanying many dermatological, neurological, and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and ...their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8-22 peptide (BAM8-22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G-protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in an Mrgpr-dependent manner. To study the sensory qualities that BAM8-22 evokes in humans, we tested the volar forearm of 15 healthy volunteers with heat-inactivated cowhage spicules previously soaked in the peptide. BAM8-22 produced itch in each subject, usually accompanied by sensations of pricking/stinging and burning. The sensations were occasionally accompanied by one or more mechanically evoked dysesthesias, namely alloknesis, hyperknesis, and/or hyperalgesia, but no wheal or neurogenic flare in the skin surrounding the application site. The inactive truncated peptide BAM8-18 produced weak or no sensations. Pretreatment of the tested skin with an antihistamine cream (doxepin) inhibited histamine-induced sensations, dysesthesias, and skin reactions but not the sensations and dysesthesias evoked by BAM8-22. We show that BAM8-22 produces itch and nociceptive sensations in humans in a histamine-independent manner. Thus, BAM8-22 may be an endogenous itch mediator that activates, in humans, MrgprX1, a novel target for potential anti-itch treatments.
Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling ...in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase-positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.
Itch is a unique sensory experience that is encoded by genetically distinguishable neurons both in the peripheral nervous system (PNS) and central nervous system (CNS) to elicit a characteristic ...behavioral response (scratching). Itch interacts with the other sensory modalities at multiple locations, from its initiation in a particular dermatome to its transmission to the brain where it is finally perceived. In this review, we summarize the current understanding of the molecular and neural mechanisms of itch by starting in the periphery, where itch is initiated, and discussing the circuits involved in itch processing in the CNS.
Dong and Dong summarize the current understanding of the molecular and neural mechanisms of itch. The authors first review the peripheral mediators that activate itch sensory neurons and then outline the circuits involved in itch processing in the CNS.
Primary sensory neurons in the DRG play an essential role in initiating pain by detecting painful stimuli in the periphery. Tissue injury can sensitize DRG neurons, causing heightened pain ...sensitivity, often leading to chronic pain. Despite the functional importance, how DRG neurons function at a population level is unclear due to the lack of suitable tools. Here we developed an imaging technique that allowed us to simultaneously monitor the activities of >1,600 neurons/DRG in live mice and discovered a striking neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury. This coupled activation occurs among various neurons and is mediated by an injury-induced upregulation of gap junctions in glial cells surrounding DRG neurons. Blocking gap junctions attenuated neuronal coupling and mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and contributes to pain hypersensitivity by “hijacking” neighboring neurons through gap junctions.
•Tissue injury induces DRG neuronal coupling that adjacent neurons activate together•The coupled activation is mediated by an injury-induced upregulation of gap junctions•DRG neuronal coupling contributes to pain hypersensitivity•Inhibiting gap-junction-mediated coupling may provide a way to relieve chronic pain
Using in vivo DRG imaging, Kim et al. discovered a neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury. This coupled activation, mediated by an upregulation of gap junctions in the DRG, contributes to pain hypersensitivity.
Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different ...activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.
Quorum-sensing molecules (QSMs) are secreted by bacteria to signal population density. Upon reaching a critical concentration, QSMs induce transcriptional alterations in bacteria, which enable ...virulence factor expression and biofilm formation. It is unclear whether mammalian hosts can recognize QSMs to trigger responsive antibacterial immunity. We report that mouse mast-cell-specific G-protein-coupled receptor Mrgprb2 and its human homolog MRGPRX2 are receptors for Gram-positive QSMs, including competence-stimulating peptide (CSP)-1. CSP-1 activates Mrgprb2 and MRGPRX2, triggering mast cell degranulation, which inhibits bacterial growth and prevents biofilm formation. Such antibacterial functions are reduced in Mrgprb2-deficient mast cells, while wild-type mast cells fail to inhibit the growth of bacterial strains lacking CSP-1. Mrgprb2-knockout mice exhibit reduced bacterial clearance, while pharmacologically activating Mrgprb2 in vivo eliminates bacteria and improves disease score. These findings identify a host defense mechanism that uses QSMs as an “Achilles heel” and suggest MRGPRX2 as a potential therapeutic target for controlling bacterial infections.
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•The mammalian receptor Mrgprb2 and MRGPRX2 can detect bacterial QSMs•QSM detection by Mrgprb2 and MRGPRX2 in mast cells elicits antibacterial mediator release•Mrgprb2 recognition of QSMs is critical for an effective immune response to bacteria•Pharmacologic activation of Mrgprb2 and MRGPRX2 enhances bacterial clearance
Bacteria use quorum-sensing signaling for cross-species communication. Pundir et al. report that host mast cells detect Gram-positive-bacteria-derived quorum-sensing molecules via the Mrgpr receptors. Mrgpr activation triggers antibacterial activity and immune cell recruitment to efficiently clear bacteria, while animals deficient in Mrgpr are hypersusceptible to bacterial infection.
Pain is the most prominent symptom of osteoarthritis (OA) progression. However, the relationship between pain and OA progression remains largely unknown. Here we report osteoblast secret ...prostaglandin E2 (PGE2) during aberrant subchondral bone remodeling induces pain and OA progression in mice. Specific deletion of the major PGE2 producing enzyme cyclooxygenase 2 (COX2) in osteoblasts or PGE2 receptor EP4 in peripheral nerve markedly ameliorates OA symptoms. Mechanistically, PGE2 sensitizes dorsal root ganglia (DRG) neurons by modifying the voltage-gated sodium channel Na
V
1.8, evidenced by that genetically or pharmacologically inhibiting Na
V
1.8 in DRG neurons can substantially attenuate OA. Moreover, drugs targeting aberrant subchondral bone remodeling also attenuates OA through rebalancing PGE2 production and Na
V
1.8 modification. Thus, aberrant subchondral remodeling induced Na
V
1.8 neuronal modification is an important player in OA and is a potential therapeutic target in multiple skeletal degenerative diseases.
Many people will suffer from joint pain as they age, particularly in their knees. The most common cause of this pain is osteoarthritis, a disease that affects a tissue inside joints called cartilage. In a healthy knee, cartilage acts as a shock absorber. It cushions the ends of bones and enables them to move smoothly against one another. But in osteoarthritis, cartilage gradually wears away. As a result, the bones within a joint rub against each other whenever a person moves. This makes activities such as running or climbing stairs painful.
But how does this pain arise? Previous work has implicated cells called osteoblasts. Osteoblasts are found in the area of the bone just below the cartilage. They produce new bone tissue throughout our lives, enabling our bones to regenerate and repair. Each time we move, forces acting on the knee joint activate osteoblasts. The cells respond by releasing a key molecule called PGE2, which is a factor in pain pathways. The joints of people with osteoarthritis produce too much PGE2. But exactly how this leads to increased pain sensation has been unclear.
Zhu et al. now complete this story by working out how PGE2 triggers pain. Experiments in mice reveal that PGE2 irritates the nerve fibers that carry pain signals from the knee joint to the brain. It does this by activating a channel protein called Na
v
1.8, which allows sodium ions through the membranes of those nerve fibers. Zhu et al. show that, in a mouse model of osteoarthritis, Na
v
1.8 opens too widely in response to binding of PGE2, so the nerve cells become overactive and transmit a stronger pain sensation. This means that even small movements cause intense pain signals to travel from the joints to the brain.
Building on their findings, Zhu et al. developed a drug that acts directly on bone to reduce PGE2 production, and show that this drug reduces pain in mice with osteoarthritis. At present, there are no treatments that reverse the damage that occurs during osteoarthritis, but further testing will determine whether this new drug could one day relieve joint pain in patients.
Osteoarthritis, a highly prevalent degenerative joint disorder, is characterized by joint pain and disability. Available treatments fail to modify osteoarthritis progression and decrease joint pain ...effectively. Here, we show that intermittent parathyroid hormone (iPTH) attenuates osteoarthritis pain by inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration in a destabilized medial meniscus (DMM) mouse model. We found that subchondral sensory innervation for osteoarthritis pain was significantly decreased in PTH-treated DMM mice compared with vehicle-treated DMM mice. In parallel, deterioration of subchondral bone microarchitecture in DMM mice was attenuated by iPTH treatment. Increased level of prostaglandin E2 in subchondral bone of DMM mice was reduced by iPTH treatment. Furthermore, uncoupled subchondral bone remodeling caused by increased transforming growth factor β signaling was regulated by PTH-induced endocytosis of the PTH type 1 receptor-transforming growth factor β type 2 receptor complex. Notably, iPTH improved subchondral bone microarchitecture and decreased level of prostaglandin E2 and sensory innervation of subchondral bone in DMM mice by acting specifically through PTH type 1 receptor in Nestin
mesenchymal stromal cells. Thus, iPTH could be a potential disease-modifying therapy for osteoarthritis.
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