Substance P, a key intermediate in the pathogenes Herpetic Stromal Keratitis (148.23)

Abstract

Abstract Substance P (SP) is a pro-inflammatory neuropeptide that promotes chronic inflammation. In the current study, we ascertain the effects of blocking SP interaction with its receptor NK1R on the development of HSK lesion severity. Spantide I, a NK1R antagonist, is used for blocking SP-NK1R interaction in C57BL/6 mice after ocular HSV-1 infection. Infected mice were treated with Spantide I, either intra-peritoneally (IP) during pre-clinical (day 0-6) and clinical phases (day 7-15) or subconjuntivally (SC) during the clinical phase of the disease. Mice receiving IP or SC treatments during the clinical phase had a significant reduction in the development of corneal lesions. Corneas excised from these mice had a reduced number of neutrophils yet the number of CD4 T cells remained unchanged when compared to control mice. Additionally, IP administration of Spantide I reduced the frequency of IFNγ producing CD4 T cells in the spleen and cervical lymph nodes of infected mice, whereas SC treatments resulted in a lesser proportion of IFN-γ secreting CD4 T cells in the corneal stroma. Moreover, SC inoculation also resulted in a reduced proportion of IL-2 receptor (CD25) expressing CD4 T cells in the infected corneal tissue when compared to control mice. Taken together, our results show that blocking SP-NK1R interaction during the clinical phase of HSK inhibits the development of severe lesions by reducing CD4 T cell activation and number of neutrophils into the corneal stroma.