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Elizabeth A Berger, Cody R McWhirter, Sharon A McClellan, Linda D Hazlett, Norbert Wolf; Neutrophil Transdifferentiation as a Factor of Disease Pathogenesis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6272.
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Neutrophils (PMN) are typically dismissed for their ‘nonspecificity’, basic functions, and uncontrolled, deleterious tissue damage. However, this cell has been more recently considered a ‘decision-shaper’ of the inflammatory response with a specificity that rivals that of a lymphocyte. The current study investigates the extent to which PMN determine the resistant (BALB/c) and susceptible (C57BL/6) phenotypes after P. aeruginosa-induced ocular infection.
BALB/c and B6 mice were systemically depleted of PMN prior to ocular infection with P. aeruginosa strain 19660. Eyes were graded by clinical score and disease response was documented using a slit-lamp. In vitro stimulation assays were performed using B6- and BALB/c-derived PMN. Real-time RT-PCR and ELISA were used to assess IL-1b and MIP-2 production. Bacterial plate counts, generation of oxygen radicals and MPO were assessed to examine cell function.
After PMN depletion, most of the animals (both B6 and BALB/c) died from sepsis within 48h p.i.; however, corneas from both strains were clearer in appearance when compared to control animals as shown by slit-lamp and histopathology. When stimulated with LPS (in vitro), B6- and BALB/c-derived PMN produced similar amounts of MIP-2 at 2 and 18h, with levels increasing over time. Regarding IL-1b, BALB/c-derived PMN produced significantly more protein compared to B6 at both time points. Overall, BALB/c-derived levels were elevated early, then decreased by about 50% at 18h. Conversely, B6-derived PMN produced twice as much IL-1b at 18h compared to 2h. Given these results, we next examined PMN function, which indicated differences regarding phagocytosis, as well as production of MPO and oxygen radicals between B6- and BALB/c-derived PMN.
This study suggests that 1) B6-derived PMN may not be as effective at driving an inflammatory response, and 2) BALB/c-derived PMN may more effectively implement a restorative phase following bacterial clearance, both of which contribute to either susceptible or resistant disease outcomes. Furthermore, there are differences in PMN function/transdifferentiation between strains, leading to the observed disease outcomes. Such differences could offer therapeutic points of intervention for disease states involving the dysregulated persistence of PMN and subsequent tissue damage without eliminating the beneficial (and essential) effects of this cell type.
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