Loss of Neurokinin-1 Receptor Alters Ocular Surface Homeostasis and Promotes an Early Development of Herpes Stromal Keratitis

Gaddipati, Subhash; Rao, Pushpa; Jerome, Andrew; Burugula, Bala Bharathi; Gerard, Norma P.; Suvas, Susmit

doi:10.4049/jimmunol.1600836

Cited by 30 publications

(24 citation statements)

References 35 publications

(40 reference statements)

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“…SP-NK1R interaction is also reported to regulate the expression of E-cadherin and ZO-1 tight junction proteins in the corneal epithelial cells and thereby demonstrate its protective role in preserving the corneal epithelial barrier function (181-183). Our results showed an excessive exfoliation of the apical corneal epithelial cells in unmanipulated NK1R-/- mice, possibly because of the dysregulation in the expression or localization of adhesion/tight junction proteins in corneal epithelial cells (178). Together, these studies suggest an important physiological role of SP-NK1R interaction in maintenance of the corneal epithelium homeostasis under steady-state condition.…”

Section: Role Of Substance P In Corneal Epithelial Homeostasismentioning

confidence: 72%

“…This study suggested the role of SP in reflex tear production. Recently, we showed that mice genetically deficient for functional NK1R had reduced level of basal tears in comparison to wild type B6 mice as measured with phenol red thread test and developed dry eye disease associated clinical features (178). SP and its metabolites are reported to present in normal human tears without inducing any overt inflammation, suggesting SP may have a physiological role in maintaining the corneal epithelium homeostasis (153, 179).…”

Section: Role Of Substance P In Corneal Epithelial Homeostasismentioning

confidence: 99%

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Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis

Suvas

2017

The Journal of Immunology

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246

217

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Substance P (SP) is an undecapeptide present in the central nervous system, and the peripheral nervous system. SP released from the peripheral nerves exerts its biological and immunological activity via high affinity neurokinin 1 receptor (NK1R). SP is also produced by immune cells, and acts as an autocrine or paracrine fashion to regulate the function of immune cells. In addition to its proinflammatory role, SP and its metabolites in combination with insulin-like growth factor-1 (IGF-1), are shown to promote the corneal epithelial wound healing. Recently, we showed an altered ocular surface homeostasis in unmanipulated NK1R-/- mice, suggesting the role of SP-NK1R signaling in ocular surface homeostasis under steady state. The current review summarizes the immunobiology of SP, and its effect on immune cells and immunity to microbial infection. In addition, the effect of SP in inflammation, wound healing and corneal epithelial homeostasis in the eye is discussed.

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Section: Role Of Substance P In Corneal Epithelial Homeostasismentioning

confidence: 72%

Section: Role Of Substance P In Corneal Epithelial Homeostasismentioning

confidence: 99%

Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis

Suvas

2017

The Journal of Immunology

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246

217

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“…The corneal tissue was separated, and the tissues were flattened with four partial cuts from the limbal to central cornea. The corneal tissue was mounted with Vectashield medium containing DAPI (Vector Laboratories, Burlingame, CA) as described previously (61). Images were acquired as described above.…”

Section: Methodsmentioning

confidence: 99%

The Absence of DHHC3 Affects Primary and Latent Herpes Simplex Virus 1 Infection

Wang¹,

Mott²,

Cilluffo³

et al. 2018

J Virol

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UL20, an essential herpes simplex virus 1 (HSV-1) protein, is involved in cytoplasmic envelopment of virions and virus egress. We reported recently that UL20 can bind to a host protein encoded by the zinc finger DHHC-type containing 3 () gene (also known as Golgi-specific DHHC zinc finger protein [GODZ]). Here, we show for the first time that HSV-1 replication is compromised in murine embryonic fibroblasts (MEFs) isolated from GODZ mice. The absence of GODZ resulted in blocking palmitoylation of UL20 and altered localization and expression of UL20 and glycoprotein K (gK); the expression of gB and gC; and the localization and expression of tegument and capsid proteins within HSV-1-infected MEFs. Electron microscopy revealed that the absence of GODZ limited the maturation of virions at multiple steps and affected the localization of virus and endoplasmic reticulum morphology. Virus replication in the eyes of ocularly HSV-1-infected GODZ mice was significantly lower than in HSV-1-infected wild-type (WT) mice. The levels of UL20, gK, and gB transcripts in the corneas of HSV-1-infected GODZ mice on day 5 postinfection were markedly lower than in WT mice, whereas only UL20 transcripts were reduced in trigeminal ganglia (TG). In addition, HSV-1-infected GODZ mice showed notably lower levels of corneal scarring, and HSV-1 latency reactivation was also reduced. Thus, normal HSV-1 infectivity and viral pathogenesis are critically dependent on GODZ-mediated palmitoylation of viral UL20. HSV-1 infection is widespread. Ocular infection can cause corneal blindness; however, approximately 70 to 90% of American adults exposed to the virus show no clinical symptoms. In this study, we show for the first time that the absence of a zinc finger protein called GODZ affects primary and latent infection, as well as reactivation, in ocularly infected mice. The reduced virus infectivity is due to the absence of the GODZ interaction with HSV-1 UL20. These results strongly suggest that binding of UL20 to GODZ promotes virus infectivity and viral pathogenesis.

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“…22 The protective effects of SP on the sub-basal nerve layer are also indirect. For instance, SP reduces excessive desquamation of corneal epithelial cells 23 and promotes scavenging of detrimental oxygen reactive species from the cornea environment, as shown in diabetic mice. 24,25 Both functions are the result of the interaction between SP and its receptor NK1R.…”

mentioning

confidence: 96%

“…24,25 Both functions are the result of the interaction between SP and its receptor NK1R. [23][24][25] In support of its role in promoting wound healing, it has been shown that SP is able to improve epithelial wound healing in denervated corneas, although only when it is administered in combination with insulin-like growth factor. 26 In rats, electrical stimulation triggers sensory nerve endings to secrete SP and increases tear volume.…”

mentioning

confidence: 99%

The Effect of Aging on Nerve Morphology and Substance P Expression in Mouse and Human Corneas

Barbariga

Rabiolo

Fonteyne

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Aging impairs corneal nerve density and sensitivity. Substance P (SP), a neuropeptide secreted by sensory nerves, regulates nerve morphology and nociception. Here, we investigate the relationship between aging, nerve morphology, and SP expression in mouse and human corneas. METHODS. SP levels in mouse corneas (wild type and substance P-knockout) and human corneas and tears were quantified with an ELISA assay. Corneal total nerve length (TNL) was measured with whole-mount b3-tubulin immunofluorescence in mouse and in vivo laser corneal confocal microscopy in humans. SP and b3-tubulin stained cross-sections were used to assess the colocalization of SP and nerves in human and mouse corneas. Ocular surface nociception was assessed with a wiping test in mice. RESULTS. SP colocalizes with sub-basal neurons in mice and humans. In WT mice, SP levels decrease with age (P ¼ 0.0045, 8 vs. 52 weeks; P ¼ 0.004, 26 vs. 52 weeks) as well as TNL (P ¼ 0.018, 8 vs. 26 weeks; P ¼ 0.0001, 8 vs. 52 weeks). Knockout mice show a greater TNL reduction (8 vs. 26 weeks, P ¼ 0.0016) than WT mice. In the oldest WT and age-matched KO mice, nociception is impaired (P ¼ 0.007 and P < 0.0001, respectively), and KO mice sensitivity is restored by topical SP treatment. In humans, SP levels are reduced in old subject corneas and correlate, in tears, with age (P ¼ 0.0368); TNL also decreases in older patients (P ¼ 0.0002). CONCLUSIONS. Age-associated corneal nerve loss is paralleled by reduction of SP expression in mice and humans. SP promotes the maintenance of normal nerve morphology in the long term and modulates nociception in the cornea.

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Loss of Neurokinin-1 Receptor Alters Ocular Surface Homeostasis and Promotes an Early Development of Herpes Stromal Keratitis

Cited by 30 publications

References 35 publications

Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis

Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis

The Absence of DHHC3 Affects Primary and Latent Herpes Simplex Virus 1 Infection

The Effect of Aging on Nerve Morphology and Substance P Expression in Mouse and Human Corneas

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