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

Neurotrophins

  • 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

Conclusion

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

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