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A more recent version of this article appeared on October 1, 2008
 (Investigative Ophthalmology and Visual Science. )
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-1906
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Article

Substance P delays apoptosis, enhancing keratitis after P. aeruginosa infection

Zimei Zhou 1, Ronald P. Barrett 1, Sharon A. McClellan 1, Yunfan Zhang 1, Elizabeth Szliter 1, Nico van Rooijen 2, and Linda D. Hazlett 3*

1 Anatomy/Cell Biology, Wayne State University, Detroit, Michigan, United States
2 Department of Molecular Cell Biology, Vrije Universiteit, VUMC, Amsterdam, Netherlands
3 Department of Anatomy/Cell Biology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, Michigan, 48201, United States

* To whom correspondence should be addressed. E-mail: lhazlett{at}med.wayne.edu.


  Abstract

PURPOSE. Apoptosis was examined after P. aeruginosa corneal infection in C57BL/6 (B6, susceptible) and BALB/c (resistant) mice. METHODS. TUNEL staining, real time RT-PCR, PMN and M{phi}depletion and immunostaining were used. RESULTS. Intense TUNEL staining was seen in BALB/c vs B6 cornea at 1 vs 3 days p.i., and correlated with mRNA levels for caspase 3. TUNEL staining (with or without PMN depletion) and PMN immunostaining revealed the PMN as the major apoptotic cell for both groups. Next, B6 mice with high corneal levels of the anti-apoptotic neuropeptide, Substance P (SP), were treated with the SP antagonist, Spantide I (with/without M{phi}depletion), resulting in earlier apoptosis and diminished disease only when the M{phi}was present. To further explore SP interactions with M{phi}, cells from both groups were elicited and stimulated with lipopolysaccharide (LPS) with/without SP. LPS with SP treatment decreased the number of apoptotic M{phi} in B6, but not BALB/c mice, and correlated with reduced mRNA expression of NK-1R (major SP receptor) on BALB/c cells. In addition, mRNA expression for IL-12 was upregulated in LPS stimulated B6 M{phi}while cells from BALB/c mice expressed more IL-10. CONCLUSION. These studies provide evidence that PMN apoptosis is delayed in the cornea of B6 vs BALB/c mice after bacterial infection; that in B6 mice, blocking SP interaction with the NK-1R promotes earlier apoptosis and improves disease outcome; that M{phi}regulate PMN apoptosis; and that M{phi} from B6 vs BALB/c mice differ in expression of the NK-1R and cytokines produced after LPS challenge.

Key Words: bacteria, apoptosis, neuropeptide, cornea






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