Neuroreceptors and Mediators


  • Calcitonin gene-related peptide (CGRP) has an impact on keratinocyte (the protective barrier cells/early warning system of the skin) differentiation, cytokine expression, and apoptosis through intracellular nitric oxide (NO) modulation and stimulation of nitric oxide synthase (NOS) activity
  • Stimulation of cultured human melanocytes with CGRP, SP, or vasoactive intestinal peptide (VIP) led to increased DNA synthesis rate of melanocytes by the cAMP pathway in a concentration- and time-dependent manner mediate

Some Important part to note

  • Substance P – induces release of histamine via binding to NKR on mast cells
  • VIPneurotensin and secretin also stimulate histamine release
  • Somatostatin stimulates histamine release from human mast cells
  • NGF stimulates histamine release and senstizes transient receptor potential V1 (TrpV1)
  • mast cell activation and histamine are required for normal wound healing (probably not chronic though)
  • Ketotifen Fumarate – h1 antagonist and mast cell growth inhibitor

Substance P (SP)

  • It induces release of histamine
  • It upregulates intercellular adhesion molecule 1 (ICAM-1), which is chemotactic for neutrophils
  • It also induces release of IL2 or IL6
  • histamine regulates SP via H3 receptors on sensory nerves
  • NGF and SP are downregulated after chronic use of capsaicin (to decrease itching and pain)

Mast cells

  • Endothelin (ET) -1, -2, and -3 work on mast cells and binds to ETA and ETB
  • ET1 degranulates mast cells (TNFa IL6 VEGF and TGFB1)
  • ET1 is involved with UV radiation (such as tanning) or inflammation of mast cells
  • Have CB1 and CB2 (also on T-lymphocytes)receptors


  • TrpV helps skin barrier homeostasis
    • TrpV1 is the capsiacin receptor
    • TrpV1 is also called vanilloid receptor (VR1)
    • TrpV1 can be activated by bradykinin, prostaglandins, and NGF
    • TrpV1 can be actvated by heat
  • CB1 agonist anandamide binds to the TrpV1 receptor
    • Topical cannabinoids directly inhibit TrpV1 functional activities via a calcineurin pathway
  • TrpV2, V3, and V4 are activated by warmth/heat
    • TrpV2 by >52C, TrpV3, >33C and TrpV4 ~25C
    • TrpV4 also acts on cold recptors creating a cold feeling (by binding camphor)
    • TrpM8 (CMR1) can be stimulated by 8-28C, menthol, or icillin
  • TrpA1 (ANKTM1) van be stimulated by <17C, wasabi, horseradish, mustard, bradykinine, or THC
  • Cooling skin temperature (or using menthol) reduces itch via inhibitory effect of Aδ-fiber activation
    • Cold sensation occurs by NGF increasing TrpA1 receptors on nerve fibers
  • In the DRG, exposure to GDNF, neurturin, or artemin potentate TrpV1 function at doses 10–100 times lower than NGF.

Proteinase-Activated Receptors

  • proteinase-activated receptor-2 (PAR-2) is activated by tryptase(and other mast cell mediators) and mast cells express PAR-2
  • Activation of PAR-2 causes inflammation similar to histamine release and can cause pain

Opioid Receptors

  • There are 2 receptors, μ- and δ-receptor, found in sensory nerve ffibers
    • β-endorphin, enkephalins, and endomorphins act on capsaicin-sensitive nerve fibers to inhibit the release of inflammatory neuropeptides such as SP, neurokinin A, and CGRP
  • Opioids mediate pain response (via mechanical and thermal stimuli)
  • Morphine works on mu- and to a lesser extent kappa- and delta-opioid receptors

Cannabinoid Receptors

  • CB system can treat pain
    • CB2 agonist palmitoylethanolamine (PEA) inhibits NGF induced thermal pain, but can be inhibitied by naloxone
    • cannabinoid agonist AM1241 stimulates β-endorphin release

Nerve Growth Factor

  • Nerve growth factor regulates skin homeostasis and inflammation
    • Pain induces NGF production and release sending signals from the skin to the dorsal root ganglia (DRG) which promotes neuronal growth and sensitivity
    • NGF can enhance caspacin evoked thermal pain
    • NGF is over expressed in many chronic illnesses with pain as well as allergic diseases


Immune Circuits of the Skin

Innate Immunity

  • skin associated lymphoid tissue (SALT) and skin immune system (SIS)
  • The path the innate immunity takes is depended on a germ-line procedure
  • LPS (lipopolysaccaride) peptidoglycan and lipotechoic acid are essential for microbial function and not produced by humans
  • Mannan-binding lectins turn on the immune system against pathogens and trigger the classical complement cascade
  • Macrophage mannose and scavenger receptors make fluid around pathogens for clearance
  • Toll like receptors (TLR) are named for their recebmalnce to something in a fly’s immune system
    • TLRs, TLR4 discovered in 1997, respond differently to pathogens and help recognize pathogenic ligands derived from bacteria, vrisuses, fungi, and some nonpathogenic host proteins and synthetic compounds (like lectins in food?), for example TLR4 responds to gram-negative LPS, while TLR2 protects against gram-positive organisms
    • Activating TLRs triggers increased expression of genes coding for key components of the inflammatory response
  • IL1 leads to activation of NF-kB (a nuclear transcription factor responsible for the induction of chemokines, cytokines, costimulatory molecules, adhesion molecules, and major histocompatability complex (MHC) molecules)
  • TLR signaling pathways may also depend on MyD88
    • TLRs act on Langerhans cells, dermal dendritic cells, keratinocytes, and mast cells
  • Bone marrow-derived antigen presenting cells (APCs) are called Langerhans cells (LC) in the epidermis and dermal dendritic cells in dermis
    • LC are neural agenst and exhaust melanocytes
    • LC have Fe recebors (that bind immunoglobulin constant regions), C3 complement receptors, and MHC class II molecules
    • LC are phagocytic and help skin drain lymph nodes

Denditic Cells

  • APCs initiate and direct the adaptive immunity
  • TLR1, 2, 4, 5 and 9 make dendritic cells sensitive to bacterial LPS, lipoproteins, glycolipids, flagellin, and CpG DNA
  • Langerhans cells don’t bind via bacteria on TLR2, 4 and 5, but do on TLR7
    • Langerhans cells to LPS and viral antigens relative to splenic dendritic cells and peritoneal macrophages
    • Langerhans cells can not be stimulated to release interferon (IFN)-γ, important in recruiting type 1 helper (Th1) T cells, but were relatively prolific secretors of chemokines that promote the type 2helper (Th2) response
    • Langerhans cells may respond epidermal milieu (e.g., keratinocytes and cytokines), instead of initiating inflammation
    • Langerhans cells may downregulate the inflammatory response


  • Keratinocyte cells create a network of tight, intercellular adhesions which are the initial barrier to exogenous injury and prevent dessication
    • Keratinocytes in the immune system can be triggered mechanically (e.g., through trauma), photochemically (e.g., by ultraviolet radiation (UVR) ), and chemically (via receptor-medi- ated response), serving to initiate inflammation and to couple the innate and adaptive arms of immunity.
    • They secrete pro-inflammatory cytokines, including interleukin(IL)-1α and tumor necrosis factor (TNF)-α.
  • UVR enhances TNFa release
  • IL-1α is upregulated by physical injury, resulting in the nuclear factor (NF)- κB-mediated activation of more than 90 known gene targets in skin
  • keratinocytes once stimulated by IL-1 can be then stimulated by GMCSF(ganulocyte-macrophage colony stimulating factor)
    • Keratinocytes can secrete IL-6, IL-7, IL-12, IL-15, and IL-18, all of which can promote and shape the adaptive immune response
  • IL-1 receptor antagonist (IL-1ra) is found in high concentrations in keratinocytes
  • IL-10 has also been shown to be inducible in keratinocytes exposed to UVB radiation

Mast Cells

  • They degranulate in response to the cross-linking of FcεR receptors by IgE, and releasing preformed histamine and TNF-α, prostaglandins, and leukotrienes
    • mast cells prolifically secrete cytokines – Th2-promoting interleukins, IL-4, IL-5, and IL-13, and Th1-related factors, including IFN-γ, IL-12, and IL-18, as well as numerous chemokines and growth factors
    • Mast cell-derived IL-1, TNF-α, and histamine have clear impact on the permeability of the vascular endothelium

The Integrated Innate Response


  • Substance P is a vasoactive peptide
  • natural killer cells act on viral infections to identify and destroy affected host cells, which depend on immunogloublin receptors and molecules sensitive to the downregulation of MHC-I peptides on their host targets
  • Complement fragments (proteins that bind invading microorganisms, either perforating their cellular membranes or coating them for subsequent phagocytosis) are chemoattractive to neutrophils and stimulatory for degranu- lation of mast cells
    • Complement proteins/fragments active TLRs and Antimicrobial peptides(AMPs)
      • AMPs are genetically encoded molecules that contribute to the cutaneous “chemical barrier” protecting expose skin surface
      • human β-defensins (hBDs) and cathelicidins are both AMPs in the skin
      • Other cells can produce AMPs as well
  • hBDs and cathelicidins have been shown to attract dendritic cells, T lymphocytes, neutrophils, monocytes/macrophages, and mast cells
    • They also help in wound healing

The Interface between Innate and Adaptive Immunity

  • Cytokines of the innate immunity also develop/activate professional APCs
  • Relying on the NF-kB pathway, dendritic cells activated by keratinocyte-derived TNF-α, IL-1α, and IL-18 (or also activated by TLRs on APCs) are primed for effective antigen presentation to naïve T lymphocytes through a process that includes:
    • the enhancement of phagocytic activity
    • the upregulation of costimulatory molecules CD40, CD80, and CD86
    • increased cell-surface expression of class II MHC molecules
    • height- ened expression of chemokine receptors responsible for localizing dendritic cells to T cell-rich areas
    • the production of cytokines that aid in directing the T cell response (e.g., IL-12, IL-18, and IL-10)
  • T lymphocytes can bind almost any protein antigen (genetic recombination after T cells go from bone marrow to the thymus)
    • T cell receptors (TCRs) are membrane-bound heterodimers of either α/β or γ/δ subunits that recognize peptide fragments presented on MHC or MHC-like molecules
    • Most T lymphocytes express α/β TCRs
    • CD4 or CD8 on the surface of α/β T cells mediate TCR and MHC-antigen complexes
    • CD4+ cells interact with MHC class II molecules and CD8+ interacts with MHC-I (in viral infections)
    • In healthy epidermis, CD8+ cells outnumber CD4+ cells; in the dermis, these are more evenly distributed
    • CD4+ cells enhance the phagocytic attack on microbes and guides the flexible adaptive immune response
  • TLR- and cytokine- activated cutaneous dendritic cells downmodulate the expression of E-cadherin (surface adhesion molecule with high avidity for keratinocytes), then once mature bind and prime naïve CD4+ cells expressing appropriate TCRs

Completing the Cutaneous Immune Circuit

  • IL-12 and IL-23 stimulate the differentiation of activated CD4+ cells into Th1 cells (releasing IL2IFNgamma and TNFalpha, promoting T cell proliferation, reinforce the antimicrobial capacity of phagocytes, and induce the differentiation of cytotoxic lymphocytes)
  • IL-4 drives the conversion of activated T-helper cells into Th2 cells – these secrete IL-4, IL-5, IL-6, and IL-10, important in quelling inflammation, as well as in stimulating eosinophils and B cells (not present in healthy human skin)
    • Th2 cells fight parasites and are part of the allergic reaction usually
  • Some CD4+ cells don’t become effectors and instead become Memory T cells (enable a rapid secondary immune response in the setting of reinfection)
  • cutaneous lymphocyte- associated antigen (CLA) is a carbohydrate cell–surface receptor found on roughly 90% of cutaneous T cells during inflammation and only sparsely expressed on non-skin-homing T lymphocytes
    • CLA can bring about cytokines i.e. (CXCR2, CCR4, CCR6, CXCR3, and CCR10)
    • CLA-marked T cells are involved with skin diseases such as psoriasis, allergic contact dermatitis, atopic dermatitis, cutaneous graft-vs.-host disease, and cutaneous T-cell lymphoma
  • After pro-inflammatory cytokines are diluted, suppressive factors such as IL-10 and TGF-β predominate
  • dendritic cells support the differentiation of regulatory T-helper sub- types, including Treg and Tr1 cells
  • regulatory cells inhibit inflammation and T cell proliferation through both direct contact and secretion of IL-10 and TGF-β

Modulation of Immune Cells by Products of Nerves

Neuroimmunocutaneous System (communication of neuropetides and cytokines via the skin)

  • nerves innervate the epidermis in close relationship with Langerhans cells (LCs), Merkel cellskeratinocytes, and mast cells
  • Neuropeptides affect the function of immune cells in multiple manners

Contact Hypersensitivity (CHS) and Delayed-Type Hypersensitivity (DTH)

  • Contact hypersensitivity (CHS) and delayed-type hyper- sensitivity(DTH) are T cell mediated immune reactions.
  • After sensitization with hapten, LCs (and/or dermal dendritic cells) migrate to regional lymph nodes where they present antigen to T cells.
    • Later, elicitation mobilizes memory T cells for a specific immune response on sub- sequent challenge with the antigen.
  • CHS can be abolished by destroying nerve fibers and draining lymph nodes. It can be restored supplying the LN with injected substance P (SP)
    • SP augments CHS responses while CGRP inhibits CHS responses
      • SP injections enhance CHS
      • Neurokinin-1 (NK-1) is the primary receptor for SP
      • SP plays a role in the inflammation response
    • pituitary adenylate cyclase-activating polypeptide (PACAP) also inhibits CHS
  • CGRP can inhibit DTH
    • IL-10 mediates the functional effects of CGRP
    • PACP and VIP also inhibit DTH

In Vitro Antigen Presenting Function

  • CGRP inhibits CHS and DTH
  • CGRP, PACP, and VIP inhibit antigens to Th1 (in LC cultures)

Langerhans Cells and CHS

  • Langerhans Cells (LC) is important for CHS reactions, playing a suppressive role

Ultraviolet Radiation-Induced Immunosuppression

  • Chapter 14 will have more
  • UVR supresses induction of CHS (possibly via CGRP) and causes immunosupression
  • CGRP decreases the number of LCs in the skin after UVR exposure
  • UVR also causes release of TNFa from mast cells (from CGRP)
    • SP reverses this

Surface Molecule Expression

  • CGRP inhibits antigens (through CD86 (aka B7-2) surface molecule expression)
    • B7-2 is a costimulatory molecule
    • CGRP’s action on B7-2 can be inhibited by IL-10
  • PACAP downregulates CD86 expression
    • PACAP also downregulates B7.1 and B7.2 expression in LPS/IFNgamma activated macrophages
  • SP is pro inflammatory by altering surface molecule expression on dermal microvascular endothelial cells
    • SP augments ICAM-1 (intracellular adhesion molecule 1), VCAM-1(vascular cell adhesion molecule 1) and ELAM-1 (endothelial-leukocyte adhesion molecule) to produce inflammation
  • VIP down-regulates CCR7

Cytokine Secretion

  • CGRP supresses immune responses by reducing TH1 immune response
    • CGRP upregulates IL10 and downregulates IL1b
  • SP boots the inflammatory response by poosting inflamamtory cytokines and downregulating anti-inflammatory cytokines
  • IL-10 suppresses TH1 cell mediated immunity (and can reduce contact hypersenstivity)
    • PACAP and VIP are immunosupressive since they help IL-10 secretion in LCs
  • IL-1b can be inhibited by CGRP
    • PACAP and VIP inhibit IL-1b
    • SP directly binds to macrophages and augments the release of IL1 (and other proinflammatory molecules)
  • IL-12 and IL-23 are part of TH1 cell-mediated immunity
    • CGRP inhibits IL12 and IL23
    • VIP can also inhibit IL12 and IL23
  • Mast cells release TNFa when CGRP is present (possibly mediating the full anti-inflammatory response)

Intracellular Mechanisms

  • Many neuropeptides activate specific G protein-couple receptors, activating cAMP-protein kinase A or the phosphatidylinositolprotein kinase C pathways
    • CGRP, VIP, and PACAP act through increasing intracellular cAMP levels
    • cAMP-protein kinase A is a pathway that downregulates or inhibits the amplification and effector phases of immune responses in T, B, and macrophage cells
    • cAMP-dependent, VIP and PACP can act via a cAMP-independent pathway, which inhibits NF-kB activation
    • SP acts through NF-kB, nuclear factor of activated T-cells (NFAT), cAMP responsive element (CRE), and activator protein-1 (AP-1)

Mast Cells

  • Neuropeptides modulate mast cell functions
  • Mast cells hang out close to SP releasing fibers and endothelial cells
    • SP released from neurons and keratinocytes can participate in mast-cell-neurite communication (suppporting bidirectional signaling between neurons and immune cells)
    • SP and CGRP fibers are commonly found in atopic dermatitis and nummular eczema
    • SP promotes mast cell degranulation (releasing tryptase by proteinase-activated receptor 2 (PAR2)), histamine release, and TNFa expression

T Lymphocyte Function

  • CGRP can inhibit T cell fuctions by supressing T cell proliferation and IL-2 production
    • SP is immunostimulatory in T cells, augmenting proliferation of T lymphocytes, enhancing IL-2 expression in T cells
    • VIP is anti-inflammatory by inhibiting T cell IL2 secretion and helping TH2 cells survive
    • PACP promotes a shift from TH1 pro-inflammatory to TH2 differentiation
    • VIP increases T regulatory cells expressing oxp3 and the CD4+CD25+ phenotype
    • These T-reg cells inhibit t-cell proliferation, impair DTH responses, and prevent graft-vs-hose disease

B Lymphocyte Function

  • Neuropetitdes modulate B cell differentiation and immunoglobulin (Ig) expression
  • CGRP inhibits surface ig expression
  • SP stimulates Ig secretion of B cells

Other Immune Cell Functions

  • CGRP inhibits neutrophils
    • CGRP inhibits natural killer cell activity. and neutrophil accumulation
  • SP stimulates neutrophils
    • SP auguments neutrophil chemotaxis, neutrophil lysosomal enzyme release, and augments neutrophil and macrophage phagocytosis
    • High SP can induce eosinophil activation, adherence,and migration


  • Immune cells produce and respond to neurotrophincs such as NGF, BDNFneurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5)
  • Target cells of neurotrophins are not limited to neurons but immune cells express neurotrophins and their receptors
  • NGF serum is high in atopic dermatities
    • NGF can cause inflammation in the skin
    • NGF can stimulate substance SP expression
    • NGF regulates mRNA expression of SP and CGRP
    • SP and neurokinin A regulate NGF synthesis
    • NGF can regulate SP and CGRP


  • SP generally augments cellular immunity, increasing T cell proliferation, pro-inflammatory cytokine release and leukocyte migration
  • CGRP, VIP, and PCAP inhibit CHS and DTH

Photoneuroimmunology: Modulation of the Neuroimmune System by UV Radiation


  • Sunlight contains
    • visible light (400–700 nm)
    • ultraviolet radiation (UVR)
      • UVA radiation as 400–320 nm ~95%
      • UVB radiation as 320–290 nm ~5%
      • UVC radiation as 290–200nm ~0% (blocked by ozone)
  • UVR is immunomodulatory
    • immune responses in neuropeptide-depleted mice are not suppressed by UVR
    • Caspaicin (w/in 48hr of UVR) reversed effect
    • Neuropeptides and neuroendocrine hormones both contribute to UV-induced immunomodulation, as well as to adaptive responses of skin to UV.

Photoneuroimmunology, Health, and Disease

  • Tumors develop in mice treated with a carcinogenic dose of UVR
    • UVR induces DNA damage and also modulates the immune system
    • Being on immunosupressants make UVR damage worse for predisposing your to cancer
    • UVR-induced immunomodulation protects against over-zealous responses to nuclear antigens exposed by UVR-killed (sunburn) cells
  • UVR is used to treat psoriasis
    • It can suppress the immune system – affects response to vaccines and infectious agents
    • individuals living at low latitudes may have an enhanced susceptibility to infectious diseases (since there is more UV)
    • living at higher latitudes have an enhanced incidence of multiple sclerosis and other autoimmune (b/c there’s a reduction in immunosuppressive UV radiation)
  • UVR increases 1,25 (OH)2 vitamin D3
  • UVR-induced local immunosuppression – involve modified antigen presentation by UVR-damaged Langerhans cells or immature dermal dendritic cells
  • systemic immunosuppression – erythemal amounts of UVR are required
  • Dermal mast cells in UV radiation – essential for UV-induced local immunosupression (and suppression of delayed type hypersensitivity responses to allogeneic spleen cells)
    • prevalence of mast cells correlates directly with their susceptibility to UV-induced systemic immunosuppression
    • There are larger concentrations of dermal mast cells (when cells carry Uvs1, a major locus for susceptibility to UV-induced immunosuppression)
    • Being mast cell-depleted, makes you non-susceptible to UV-induced systemic immunosuppression
  • Mast cells produce chemokines (such as TNFa, IL10 and Histamine)
    • Histamine can induce immunomodulation
      • It stimulates Prostaglandin E2 production
      • Prostaglandin E2 can work locally or systemically on epidermal cells in lymph nodes
      • Prostanoids are responsible for at least 50% of the systemic suppression of contact hypersensitivity responses caused by UV irradiation
      • Histamine modulates the maturation and activation of dendritic cells
    • neuropeptides are the major mechanism of IgE-independent mast cell activation

Skin Photoreceptors for UVR. Links to the Neuroimmune System

  • Very little UVB radiation penetrates skin beneath the epidermis
    • cellular DNA damage
      • cyclobutane pyrimidine dimers is the predominant DNA lesions in whole human skin exposed to UVA and UVB radiation
      • UVR damage makes LCs worse at presenting antigens (in lymph nodes) – suppressing immunity to the antigen and inducing regulatory cells and tolerance to antigens
    • oxidation of membrane proteins
      • UVR causes the oxidation of phosphatidylcholine in the membranes of irradiated skin cells
        • oxidized phosphatidylcholine binds to, and activates:
          • receptors for platelet activating factor on cells
          • Which activates MAP kinases, phospholipases, and gene transcription
    • alterations to intracellular signaling events
  • trans-urocanic acid (Trans-UCA [deaminated histidine]) – molecular species located superficially in the stratum corneum of skin
    • It is converted to its more soluble cis isomer, when exposed to UVR
    • Helps cause immunosuppression by UVR
    • UCA isomers in human urine may be a biomarker of recent UVA/UVB radiation exposure
    • cis-UCA also modulates the immune system in UV-induced cells

Stimulation by cis-Urocanic Acid of Neuropeptide Release from Peripheral Sensory Nerves

  • cis-UCA, but not trans-UCA, can activate sensory nerves in skin to release neuropeptides
    • cis-UCA increases microvascular (blood) flow
    • cis-UCA relies on neuropeptides, substance P, and calcitonin gene-related peptide (CGRP), or else it is not immunomodulatory
    • cis-UCA can reduce immune response to hapten
    • cis-UCA binds competitively to receptors for γ-amino-butyric acid(GABA), but doesn’t change blood flow
    • cis-UCA binds a histamine receptors, but doesn’t change blood flow
    • cis-UCA binds to the 5-hydroxytryptamine (5-HT)2A receptor
    • cis-UCA suppresses lipopolysaccharide-induced TNFα production by human monocytes

Immunoregulatory Properties of UVR/ cis-Urocanic Acid-Induced Neuropeptides – Calcitonin Gene-Related Peptide

  • UVR-induced CGRP is responsible (CRITICAL) for some suppressive properties of UVB on local contact hypersensitive responses
    • CGRP can reduce Ia-positive epidermal antigen presenting cells
    • CGRP reduces immunoregulation caused by a single (and multiple) erythemal dose of UV
    • CGRP downregulates LCs (major antigen presenting cells of the epidermis)
      • increases production of cyclic AMP by adenylate cyclase and augmentation of lipopolysaccharide- and granulocyte-macrophage colony stimulating factor-induced IL-10 production
      • IL-10 downregulates CD86 and inhibits antigen presentation by Langerhans cells

Stress and Urticaria


  • Urticaria (hives)
    • localized wheals (a red, swollen mark left on flesh) to widespread recurrent whealing and angioedema
    • 15-20% of world pop get it at least once in their life
    • Superficial or deeper
    • usually pruritic and often pale in the center because of intense edema, before maturing into pink superficial plaques
    • resolve/gone after 2-24hr (unless damage by excoriation)
    • so usually acute
    • Angioedema -more painful than itchy, and generally takes longer time to resolve
    • 2x/wk for 6 weeks = chronic urticaria
  • Mediators
    • histamine
      • mast cells degranulate to release histamine
    • Emotional factors does not exacerbate cold urticaria
  • Adrenergic urticaria
    • stress induced
    • reproduced with injection of epinephrine and norepinephrin and a beta-blocker, propranlol
    • may coexist with cholinergic urticaria

Role of Psychosocial Stress

  • urticaria can be induced by (emotional) stress
    • acute emotional form
      • follows specific events with a clear cause-effect relationship
    • chronic recurrent form
      • psychodynamic basis as a psychosomatic disease
  • Biomarker – Immunological tests (IgE) is <20% of cases
  • Biomarker – Low serum dehydroepiandrosterone sulfate (DHEA-S)
    • lower DHEA S may mean greater psychological distress amplification
    • Also look at DHEA-S/cortisol ratio

Types of Stress

  • emotional or psychological factors
  • stressful or catastrophic major life events
  • traumatic life events such as abuse and/or neglect during childhood and later life
  • urticaria vs quality of life of patient

Personality Variables and Psychodynamic Formulations

  • Some old theories
    • nervous excitement was associated with the onset of urticaria
    • the vascular reactions in the disease are the same as those that occur after actual trauma to the skin
    • at the time the urticarial reaction occurs the patient appears to be hung dead center between the extremes of passivity and aggression, immobilized in his conflict betwixt abject dependence and destructive rage

Psychological Factors

  • some more old theories
    • a feeling of being wronged or injured, usually by someone in a close family relationship – brought on urticaria
  • The skin temperature and response to mechanical stimuli increased and the reactive hyperemia threshold decreased
    • an increased tendency of both arterioles and minute vessels to dilatation

Skipping (or going super brief) these chapters as it seems self explanatory

  1. Stress from Life Events
  2. Traumatic and Catastrophic Life Events
  3. Childhood Abuse and Developmental Trauma
  4. Urticaria as a Conditioned Response
    • you can get urticaria as an allergic response (i.e. food)


  • The skin has it’s own HPA axis
    • local expression of corticotropin releasing hormone (CRH) and receptors receptors (CRH-R)
  • acute stress and CRH stimulate mast cells
    • this increases vascular permeability through CRH-R1 activation
    • Acute stress increasing CRH triggers mast cell-dependent vascular permeability
  • Major depressive disorder (MDD) and post-tramautic stress disorder(PTSD)
    • both associated with elevated CRH
    • CRH mast cell degranulation is important for symptom exacerbation in urticaria

Neuroimmunology of Atopic Dermatitis


  • eczema – keratinocyte proliferation
  • atopic dermatitis (AD) aka neurodermatitis
    • dysregulation of neuropeptides and neurotrophins
    • neuroimmune interaction is controlled by endopeptidases
      • which can terminate neuropeptide-induced inflammatory or immune responses

Neuroimmune Aspects of Atopic Dermatitis

  • In AD patients
    • tachykinin receptors have been detected on blood vessels and keratinocytes
    • NK1R expression on endothelial cells was diminished after UVA irradiation (in normal subjects)
      • NK1R expression on keratinocytes is unchanged
      • differential regulation of this receptor in different target cells by UV light and during cutaneous inflammation
      • There is an altered expression pattern of neurokinin receptors after UV-A irradiation in patients with AD
  • tachykinin substance P (SP) in AD
    • regulates proliferation and cytokine expression in monocytes after exposed to  dust mites (Der f) (in AD patients)
    • SP promotes
      • Der f- induced proliferation
        • upregulation of IL10 expression
        • downregulation of IL5 expression
        • Upregulation of IL2
    • SP and VIP are opposing on TH1 and TH2 cytokines in AD
    • Normally SP
      • increases TH2 IL2
      • Increases TH1 IFNgamma
    • VIP inhibits the above
      • increases bloodflow (when combined with ACh)
      • decreases flare area of AD (independently and also combined with ACh)
        • skin dilation is dependent on functional cholinergic fibers, but not ACh itself
      • VIP-receptor expression is down regulated in AD
      • VIP serum levels are elevated in AD
  • POMC in AD
    • α-MSH modulates IgE production and the finding of increased levels of POMC-peptides in the skin of AD patients
    • β-endorphin are clustered around μ-opioid receptor- positive nerves in AD
      • μ-opioid recep- tor expression was diminished in skin biopsies from patients with AD
  • NGF in AD
    • Nerve-growth factor (NGF) and its high- and low-affinity receptors tropomyosin-related kinase receptor (trk)A and trkB, respectively, are upregulated in the skin of AD patients
    • NGF plasma levels increased
      • induced release of histamine and tryptase from a mast cell line (HMC-I)
    • NGF may regulate mast cell–nerve and keratinocyte– nerve interactions in the skin in AD
  • Neurotrophin 4 (NT-4) in AD
    • induced by IFN-gamma
    • increased expression (not increased NT3 expression)
    • NT4 found in epidermis, NT3 found in dermal compartment
  • Neurovascular Aspects of Atopic Dermatitis
  • AD has a problem with excess vasoconstriction (instead of vasodilation)
    • would NO help?
    • It is triggered by
      • mechanical stimuli (white dermographism)
      • chemical stimuli  (i.e., acetylcholine ACh)
    • There is prolonged vasoconstriction to cold/lower temperature
      • would IR help?
  • TH1 to TH2 of AD is influenced by stress
    • ie neuronal manipulation of cytokines, chemokines, or cell adhesion molecules
  • Other “stress” mechanisms
    • oxidative stress pathways
    • nerve–mast cell interactions
    • modulation of the synthesis and release of
      • chemokines
      • amines
      • reactive oxygen products
      • glucocorticoids
      • macrophage migration-inhibitory factor (MIF)
      • proteases
      • neuropeptides
  • Neuropeptides regulate mast cells as well as eosinophils as effector cells in AD
    • release of mediators from mast cells [IL-4tumor necrosis factor (TNF)-α, histaminetryptase].
    • neurotrophins such as NGF or brain-derived neurotrophic factor (BDNF)
  • Emotional stress exacerbates it
  • galanin and galanin-binding sites
    • neuropeptide that inhibits plasma extravasation
    • located around blood vessesls
    • upregulated in AD
  • pituitary adenylate cyclase activating polypeptide (PACAP)
    • a neuropeptide that is also a potent vasodilatator
    • regulator of human vasculature in vivo
  • Role of Nerves in the Pathophysiology of Pruritus in Atopic Dermatitis
  • Main symptom of AD is pruritus (itching)
    • localized to skin or mucous
    • can also be an extracutaneous event
    • pruritus is transmitted via excitation of neuropeptide-containing C-fibers
  • Mediators of pruritus
    • amines (histamine, serotonin in rodents)
    • prostanoids (prostaglandins, leukotrienes)
    • kinins
    • kallikreins
    • proteases (tryptase)
    • cytokines
    • protons
    • others
  • Histamine
    • mediating pruritogenic effects in urticaria
    • histamine-receptor-4 (H4R)
      • induction of itch in mice
    • H3R is involved in scratching behavior of mice
    • AD patients have an altered histamine response and a decreased ability of sensory nerves to signal itching to the CNS
  • SP makes it worse (releasing histamine)
    • proving mast cells are involved
    • same for VIPsomatostatinsecretin, and neurotensin
    • CGRP does not release histamine, but is a vasodilator
    • NK1R activation may be involved in AD
  • Injection of VIP and acetylcholine (ACh) make AD worse (dose dependent)
    • VIP is more involved than ACh
  • capsaicin helps pruritus and pain
  • morphine induces itch
  • β-endorphin (or enkephalins) – intensify histamine-induced pruritus
  • Opioid μ-receptors
    • opioid antagonist naloxone is effective in abolishing or diminishing itch
    • also involved in cholestatic pruritus
      •  5-hydroxytryptamine antagonist reduces cholestatic pruritus, but not skin-derived pruritus
        • serotonin is synthesized in platelets and melanocytes, not mast cells or nerve fibers
  • cannabinoids
    • CB1
      • agonists suppress histamine-induced pruritus
    • TRPV1
      • anandamine (endogenous cannabinoid) – activates and sensitizes TRPV1
        • this switches neuronal effect from inhibition to excitation/sensitization
    • Cannabinoid receptors are also expressed by keratinocytes
      • induce release of β-endorphins
    • TRPV1 agonist with a CB1 agonist
      • creates anti-pruritic response
      • prevents burning from capsaicin stimulation
        • CB agonists (e.g., anandamide, HU210) would prevent the excitation induced by capsaicin
  • Proteinases/proteases (ie from plants or bacteria)
    • can induce itch
    • Papain and trypsins (and tryptase)
      • induce itch responses
        • mediated by the activation of PARs
      • activated dermal mast cells (next to afferent unmyelinated C-fibers)
        • induce itch
      • Trypatse –
        • Via the activation of the G protein-coupled receptor proteinase-activated receptor-2 (PAR-2)
        • transmits itch perception and in parallel mediates neuropeptide release
        • activate mast cells through neurokinin receptors
  •  IL-31 pathway
    • increased in AD patients and ACD patients
    • IL-31 is associated with the expression of the TH2 cytokines IL-4 and IL-13
    • Receptors for IL31 and IL31 RA are highly expressed in AD
  • Therapeutic Consequences of Neuroimmune Interactions for Atopic Dermatitis
  • capsaicin
    • helpful in
      • intestinal and airway inflammation
      • arthritis
      • painful diabetic neuropathy
      • cold urticaria
      • AD
      • herpes infection
      • tumor pain
      • different forms of pruritus
    • good at reducing pain, pruritus, or neurogenic inflammation
    • reduces inflammation/flare induced by histamine or SP
    • enhances erythema (superficial reddening of the skin) responses after UV irradiation, tuberculin reaction, and contact dermatitis
  • neurokinin-1 receptor (NK1R) antagonists may be useful
  • TRPV1 antagonists may be useful
  • UVR
    • UVA irradiation
      • modulates the expression of tachykinin receptors in AD
  • Anti-depressants
    • doxepin (applied topically)
      • inhibits histamine or SP-induced wheal and/or flare
      • but may lead to allergic contact dermatitis
  • Cannabinoids
    • reduce hyperalgesia and neurogenic inflammation
      • via interaction with cannabinoid-1 (CB1) receptors and inhibition of neurosecretion (of CGRP) from peripheral terminals of nociceptive primary afferent nerve fibers
      • cannabinoid-2 (CB-2) receptor inhibition may be beneficial for the treatment of pain and itch
  • Somatostain (SST) and receptors regulate inhibitory immune repsonses
    • SMS201-995 (SST analogue peptide)
      • enhances immunosupressive effect of FK506 (tacrolimus)
    • SST after using capsaicin is anti-inflammatory for contact dermatitis
  • Protease-activated receptors (PARs)
    • anti-inflammatory by downregulatin inflammation in pruritus
  • IL-31 antagonists
    • treatment of inflammation and pruritus in AD patients