Substance P and Host Defence

Expression of substance P in alveolar epithelial cells

The tachykinin family of neurotransmitters are not only involved in central and peripheral nervous system function but also have a role in inflammation (termed neurogenic inflammation) and adaptive immunity. The most characterized member of the family is substance P (SP). This is encoded by the preprotachykinin A (PPT-A) or TAC1 locus. Alternative splicing of TAC1 RNA and processing of the propeptide yields, in addition to SP, neurokinin A (NKA) and neuropeptides K and γ. Although local nerves have been believed to be the major source of tachykinins in the peripheral tissues, TAC1 has been shown to be induced and expressed in other cell types such as monocytes, macrophages, pancreatic islet cells and various tumour cell types.This has led to the hypothesis that SP not only acts as a mediator of the neuroimmune system but is also involved in direct interaction between immune cells in a paracrine and/or autocrine fashion independent of sensory nerves. The tachykinins can modulate the immune response and SP has been shown to regulate production of a number of cytokines including IL-1, IL-6, IL-8 and TNFα to mediate inflammatory and cell proliferative responses.

We have previously addressed the actions of the TAC1 gene expression and function in virus infection in the lung and in particular early function of neuropeptides released from non neuronal cells in the lung. The tachykinins have been extensively implicated in the initiation and progression of lung disease processes such as bronchitis and asthma, although it was presumed that it was the release from sensory ganglia that was the major effector. Studies by us and others have shown that viruses (e.g. respiratory syncytial virus and murine gammaherpesvirus, MHV-68) can induce SP and neurogenic inflammation, particularly in lungs in the context of a respiratory challenge. Consistent with this NK1 is upregulated in lymphocytes (especially T cells) in the lung in response to viral infection and antibody to SP decreases inflammatory responses to pulmonary viral infection. In addition, we have shown that mice deficient in TAC1 peptides or NK-1 receptor are more susceptible to virus infection. This indicates a primary role for SP in the lung in the response to respiratory viral infection. More recently we have demonstrated in a transgenic model in which the TAC1 gene is co-expressed with the LacZ marker gene that non-neuronal TAC1 expression early after infection may have important clinical implications for the progression or management of lung disease or infection aside from the well characterised later involvement of the tachykinins during the inflammatory response. The action of MHV-68 is similar to that of RSV in the lung as regards tachykinin expression and function in which SP is increased and altered NK1R expression is observed. This alteration of tachykinin function and expression is observed in other challenges in the lung. We therefore view the tachykinin pathway as a key major modulator of the immune response to lung challenge.

We are currenly investigating how how substance P acts during the generations of the inflammatory response to virus infection in the lung and how this can be a therapeutic target for intervention during severe respiratory syncytical virus-associated disease.

This work is being carried out in collaboration with Prof John Quinn and the Neurotransmitter Biology group in Liverpool and Pharmnovo AB

Relevant Publications

    2013

  • Botz, B., Imreh, A., Sándor, K., Elekes, K., Szolcsányi, J., Reglodi, D., Quinn, J.P., Stewart, J.P., Zimmer, A., Hashimoto, H., Helyes, Z. (2013). Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions. Peptides. 43, 105-112. DOI: 10.1016/j.peptides.2013.03.003.[Full Text on Publisher Website]
  • Borbély, E., Hajna, Z., Sándor, K., Kereskai, L., Tóth, I., Pintér, E., Nagy, P.,  Szolcsányi, J., Quinn, J., Zimmer, A., Stewart, J.P., Paige, C., Berger, A., Helyes, Z. (2013). Role of Tachykinin 1 and 4 Gene-Derived Neuropeptides and the Neurokinin 1 Receptor in Adjuvant-Induced Chronic Arthritis of the Mouse. PLoS One, 8, e61684.[Open Access Full Text] [PDF]PDF
  • 2011

  • Quinn, J.P., Kipar, A., Hughes, D.J., Bennett, E., Cox, H., McLaughlin, L., Zimmer, A., Hunt, S.P., and Stewart, J.P. (2011). Altered host response to murine gammaherpesvirus 68 infection in mice lacking the tachykinin 1 gene and the receptor for substance P. Neuropeptides. 45, 49-53. [Full Text on Publisher Website] [PDF]PDF
  • 2010

  • Helyes, Z., Elekes, K., Sándor, K., Kereskai, L., Szitter, I., Pintér, E., Kemény, A., Szolcsányi, J.,  McLaughlin, L., Vasiliou, S., Kipar, A., Zimmer, A., Hunt, S.P., Stewart, J.P. and  Quinn, J.P. (2010). Involvement of preprotachykinin A gene-encoded peptides and the neurokinin 1 receptor in endotoxin-induced murine airway inflammation. Neuropeptides. 44, 399-406. [Full Text on Publisher Website] [PDF]PDF
  • 2008

  • Stewart J.P., Kipar, A., Cox, H., Payne, C., Vasiliou, S., Quinn, J.P. (2008). Induction of tachykinin production in airway epithelia in response to viral infection. PLoS ONE. 3, e1673. [Open Access Full Text] [PDF]PDF
  • 2007

  • Semple, M.G., Ebrahimi, B., Dankert, H.M., Correia, J.B., Booth, J.A., Stewart, J.P., Smyth, R.L., Hart, C.A. (2007). Severe respiratory syncytial virus bronchiolitis in infants is associated with reduced airway interferon-γ and substance P. PLoS ONE .2, e1038. [Open Access Full Text] [PDF]PDF
  • 2006

  • Spencer, E., Chandler, K.E., Haddley, K., Howard, M.E., Hughes, D.J., Belyaev, N.D., Coulson, J.C., Stewart, J.P., Buckley, N.J., Kipar, A., Walker, M.C., Quinn, J.P. (2006). Regulation and role of REST and REST4 variants in modulation of gene expression in vivo and in vitro in epilepsy models. Neurobiology of Disease. 24, 41-52. [Open Access Full Text] [PDF]PDF
  • 2001

  • Payne, C.M., Heggie, C., Brownstein, D., Stewart, J.P., and Quinn, J.P.  (2001). Role of Tachykinins in the Host Response to Murine Gammaherpesvirus Infection. Journal of Virology, 75, 10467-10471. [Open Access Full Text] [PDF]PDF