Stretching the Function of Innate Immune Cells

The importance of innate immune cells to sense and respond to their physical environment is becoming increasingly recognized. Innate immune cells (e.g. macrophages and neutrophils) are able to receive mechanical signals through several mechanisms. In this review, we discuss the role of mechanosensitive ion channels, such as Piezo1 and transient receptor potential vanilloid 4 (TRPV4), and cell adhesion molecules, such as integrins, selectins, and cadherins in biology and human disease. Furthermore, we explain that these mechanical stimuli activate intracellular signaling pathways, such as MAPK (p38, JNK), YAP/TAZ, EDN1, NF-kB, and HIF-1α, to induce protein conformation changes and modulate gene expression to drive cellular function. Understanding the mechanisms by which immune cells interpret mechanosensitive information presents potential targets to treat human disease. Important areas of future study in this area include autoimmune, allergic, infectious, and malignant conditions.

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Role of Gangliosides in Peripheral Pain Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21031005 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1005 ◽

Cited By ~ 4

Author(s):

Péter Sántha ◽

Ildikó Dobos ◽

Gyöngyi Kis ◽

Gábor Jancsó

Keyword(s):

Ion Channels ◽

Intracellular Signaling ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Membrane Receptors ◽

Transient Receptor Potential Vanilloid ◽

Pain Mechanisms ◽

Novel Approach ◽

Transient Receptor ◽

Nociceptive Ion Channels

Gangliosides are abundantly occurring sialylated glycosphingolipids serving diverse functions in the nervous system. Membrane-localized gangliosides are important components of lipid microdomains (rafts) which determine the distribution of and the interaction among specific membrane proteins. Different classes of gangliosides are expressed in nociceptive primary sensory neurons involved in the transmission of nerve impulses evoked by noxious mechanical, thermal, and chemical stimuli. Gangliosides, in particular GM1, have been shown to participate in the regulation of the function of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1), a molecular integrator of noxious stimuli of distinct nature. Gangliosides may influence nociceptive functions through their association with lipid rafts participating in the organization of functional assemblies of specific nociceptive ion channels with neurotrophins, membrane receptors, and intracellular signaling pathways. Genetic and experimentally induced alterations in the expression and/or metabolism of distinct ganglioside species are involved in pathologies associated with nerve injuries, neuropathic, and inflammatory pain in both men and animals. Genetic and/or pharmacological manipulation of neuronal ganglioside expression, metabolism, and action may offer a novel approach to understanding and management of pain.

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Proteinase-Activated Receptor-4 (PAR4) Activation Leads to Sensitization of Rat Joint Primary Afferents Via a Bradykinin B2 Receptor-Dependent Mechanism

Journal of Neurophysiology ◽

10.1152/jn.00486.2009 ◽

2010 ◽

Vol 103 (1) ◽

pp. 155-163 ◽

Cited By ~ 32

Author(s):

Fiona A. Russell ◽

Victoria E. Veldhoen ◽

Dmitri Tchitchkan ◽

Jason J. McDougall

Keyword(s):

Firing Rate ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Receptor Activation ◽

Primary Afferents ◽

Knee Joints ◽

Transient Receptor Potential Vanilloid ◽

Mechanical Stimuli ◽

Male Wistar Rats ◽

Normal Rat

The G-protein-linked receptor, proteinase-activated receptor-4 (PAR4) is activated by proteinases released into the joint during inflammation. It is unclear whether PAR4 has a pro- or anti-nociceptive effect and whether it directly affects nerve activity. In this study, we examined the expression of PAR4 in joints and dorsal root ganglion (DRG) neurons and whether activation of PAR4 has an effect on nociception in normal rat knee joints. Electrophysiological recordings were made from joint primary afferents in male Wistar rats during both nonnoxious and noxious rotations of the knee. Afferent firing rate was recorded for 15 min post close intra-arterial injection of 10−9–10−5 mol of the PAR4 activating peptide, AYPGKF-NH2, or the inactive peptide, YAPGKF-NH2 (100 μl bolus). Rats were either naive or pretreated with the selective PAR4 antagonist, pepducin P4pal-10, the transient receptor potential vanilloid-1 (TRPV1) antagonist, SB366791, or the bradykinin B2 receptor antagonist, HOE140. Immunofluorescence experiments showed extensive PAR4 expression in the knee joint and in sensory neurons projecting from the joint. AYPGKF-NH2 significantly increased joint afferent firing during nonnoxious and noxious rotation of the knee. The inactive control peptide, YAPGKF-NH2 was without effect. Systemic pretreatment with the PAR4 antagonist, pepducin P4pal-10, inhibited the AYPGKF-NH2-induced increase in firing rate. Pretreatment with HOE140, but not SB366791, also blocked this increase in firing rate. These data reveal that in normal rat knee joints, PAR4 activation increases joint primary afferent activity in response to mechanical stimuli. This PAR4-induced sensitization is TRPV1-independent but involves B2 receptor activation, suggesting a role for kinins in this process.

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Activation of TRPV4 on dural afferents produces headache-related behavior in a preclinical rat model

Cephalalgia ◽

10.1177/0333102411427600 ◽

2011 ◽

Vol 31 (16) ◽

pp. 1595-1600 ◽

Cited By ~ 37

Author(s):

Xiaomei Wei ◽

Rebecca M Edelmayer ◽

Jin Yan ◽

Gregory Dussor

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Functional Expression ◽

Transient Receptor Potential Vanilloid ◽

Hypotonic Solution ◽

Mechanical Stimuli ◽

Trigeminovascular System ◽

Dural Afferents

Background: The mechanisms contributing to the pain of migraine are poorly understood although activation of afferent nociceptors in the trigeminovascular system has been proposed as a key event. Prior studies have shown that dural-afferent nociceptors are sensitive to both osmotic and mechanical stimuli. Based on the sensitivity to these stimuli we hypothesized that dural afferents express the osmo/mechano-sensitive channel transient receptor-potential vanilloid 4 (TRPV4). Methods: These studies used in vitro patch-clamp electrophysiology of trigeminal neurons retrogradely labeled from the dura to examine the functional expression of TRPV4. Additionally, we used a rat headache model in which facial/hind paw allodynia following dural stimulation is measured to determine whether activation of meningeal TRPV4 produces responses consistent with migraine. Results: These studies found that 56% and 49% of identified dural afferents generate currents in response to hypotonic solutions and 4α-PDD, respectively. The response to these stimuli indicates that dural afferents express TRPV4. Activation of meningeal TPRV4 using hypotonic solution or 4α-PDD in vivo resulted in both facial and hind paw allodynia that was blocked by the TRPV4 antagonist RN1734. Conclusion: These data indicate that activation of TRPV4 within the meninges produces afferent nociceptive signaling from the head that may contribute to migraine headache.

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TRPV1 Antagonism by Capsazepine Modulates Innate Immune Response in Mice Infected withPlasmodium bergheiANKA

Mediators of Inflammation ◽

10.1155/2014/506450 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Elizabeth S. Fernandes ◽

Carolina X. L. Brito ◽

Simone A. Teixeira ◽

Renato Barboza ◽

Aramys S. dos Reis ◽

...

Keyword(s):

Lipid Peroxidation ◽

Immune Response ◽

Natural Killer ◽

Innate Immune Response ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Innate Immune ◽

Cell Phenotype ◽

Transient Receptor Potential Vanilloid ◽

Cell Numbers

Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host’s defence to malaria. Transient receptor potential vanilloid 1 (TRPV1) modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 105red blood cells infected withPlasmodium bergheiANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80+Ly6G+cell numbers as well as activation of both F4/80+and F4/80+Ly6G+cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1+and natural killer (NK) population, without interfering with natural killer T (NKT) cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFαand IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria.

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Role of the TRPV Channels in the Endoplasmic Reticulum Calcium Homeostasis

Cells ◽

10.3390/cells9020317 ◽

2020 ◽

Vol 9 (2) ◽

pp. 317 ◽

Cited By ~ 2

Author(s):

Aurélien Haustrate ◽

Natalia Prevarskaya ◽

V’yacheslav Lehen’kyi

Keyword(s):

Endoplasmic Reticulum ◽

Calcium Homeostasis ◽

Intracellular Signaling ◽

Mammalian Cells ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Endoplasmic Reticulum Calcium ◽

Trpv Channels ◽

Transient Receptor

It has been widely established that transient receptor potential vanilloid (TRPV) channels play a crucial role in calcium homeostasis in mammalian cells. Modulation of TRPV channels activity can modify their physiological function leading to some diseases and disorders like neurodegeneration, pain, cancer, skin disorders, etc. It should be noted that, despite TRPV channels importance, our knowledge of the TRPV channels functions in cells is mostly limited to their plasma membrane location. However, some TRPV channels were shown to be expressed in the endoplasmic reticulum where their modulation by activators and/or inhibitors was demonstrated to be crucial for intracellular signaling. In this review, we have intended to summarize the poorly studied roles and functions of these channels in the endoplasmic reticulum.

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