Neuroimmunology of Atopic Dermatitis

Introduction

  • 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

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