McNeill, E.; (2006) Neutrophil function in S100A9 null mice. Doctoral thesis , University of London.

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Abstract

S100A9 and its heterodimeric binding protein, S100A8, are low molecular weight calcium-binding proteins of the SI00 protein family that are abundantly expressed in myeloid cells. They constitute 40% of neutrophil cytosolic protein and 1% of monocyte cytosolic protein. To elucidate the function of this protein complex, a study of the S100A9 null mice, which also lack S100A8, was undertaken. Myelopoiesis in the S100A9 null mice was shown to be normal, with the resulting neutrophils and monocytes showing no differences in differentiation or activation state. No compensatory upregulation of other SI00 proteins was found in S100A9 null neutrophils, which exhibit a significantly lower buoyant density than wildtype neutrophils. The basic calcium homeostasis of the S100A9 null neutrophils was normal. However a reduced calcium flux in response to suboptimal levels of MIP-2, KC, MlP-la, PAF and C5a but not FMLP was observed. This lesion in calcium response was shown to be in the IP3-mediated calcium release pathway. Adhesion of the S100A9 null neutrophils along with migration and in vitro chemotaxis was normal. In addition no differences in the cytoskeletal morphology of the S100A9 null cells was seen. No defect in in vivo migration of neutrophils or monocytes could be seen in a peritonitis model initiated by thioglycollate, TNFa or IL-ip. Activation of the NADPH oxidase, measured in kinetic and phagocytosis- activated studies, was unaltered by the loss of S100A9. There was no effect of S100A9 deletion in an in vitro bacterial killing assay or in an in vivo model of Streptococcus pneumoniae lung infection. Expression of S100A8/9 has been associated with wound healing and cancer. No defect in wound healing or injected tumour growth was found in S100A9 null mice. However a model of chemical-induced carcinogenesis in the S100A9 null mice demonstrated both an increased rate of papilloma formation and increased papilloma multiplicity.

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