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Myeloid cell function in MRP-14 (S100A9) null mice
Josie A R Hobbs1, Richard May, Kiki Tanousis
1Leukocyte Adhesion Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, United Kingdom.
Abstract:
Myeloid-related protein 14 (MRP-14) and its heterodimeric partner, MRP-8, are cytosolic calcium-binding proteins, highly expressed in neutrophils and monocytes. To understand the function of MRP-14, we performed targeted disruption of the MRP-14 gene in mice. MRP-14(-/-) mice showed no obvious phenotype and were fertile. MRP-8 mRNA but not protein is present in the myeloid cells of these mice, suggesting that the stability of MRP-8 protein is dependent on MRP-14 expression. A compensatory increase in other proteins was not detected in cells lacking MRP-8 and MRP-14. Although the morphology of MRP-14(-/-) myeloid cells was not altered, they were significantly less dense. When Ca(2+) responses were investigated, there was no change in the maximal response to the chemokine MIP-2. At lower concentrations, however, there was reduced responsiveness in MRP-14(-/-) compared with MRP-14(+/+) neutrophils. This alteration in the ability to flux Ca(2+) did not impair the ability of the MRP-14(-/-) neutrophils to respond chemotactically to MIP-2. In addition, the myeloid cell functions of phagocytosis, superoxide burst, and apoptosis were unaffected in MRP-14(-/-) cells. In an in vivo model of peritonitis, MRP-14(-/-) mice showed no difference from wild-type mice in induced inflammatory response. The data indicate that MRP-14 and MRP-8 are dispensable for many myeloid cell functions.
Insights
Myeloid-related protein 14 (MRP-14) is crucial for MRP-8 protein stability but dispensable for myeloid cell functions like chemotaxis and inflammation. MRP-14 knockout mice show normal responses in peritonitis models.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Myeloid-related protein 14 (MRP-14) and MRP-8 are cytosolic calcium-binding proteins abundant in neutrophils and monocytes.
- Their specific roles in myeloid cell function remain incompletely understood.
Purpose of the Study:
- To investigate the in vivo function of MRP-14 by creating and analyzing MRP-14 gene-targeted knockout mice.
- To determine the impact of MRP-14 deficiency on myeloid cell stability, calcium signaling, and inflammatory responses.
Main Methods:
- Targeted gene disruption of the MRP-14 gene in mice.
- Analysis of myeloid cell morphology, density, and protein expression (MRP-8).
- Assessment of calcium (Ca2+) flux, chemotaxis, phagocytosis, superoxide burst, apoptosis, and in vivo peritonitis models.
Main Results:
- MRP-14 knockout mice (MRP-14-/-) exhibited normal phenotypes and fertility.
- MRP-8 protein levels were reduced in MRP-14-/- myeloid cells, indicating dependence on MRP-14 for stability.
- While maximal Ca2+ responses were unchanged, lower-concentration responses to MIP-2 were reduced in MRP-14-/- neutrophils, without affecting chemotaxis.
- Myeloid cell functions including phagocytosis, superoxide production, apoptosis, and in vivo inflammatory responses were unaffected.
Conclusions:
- MRP-14 is essential for MRP-8 protein stability but not for the overall viability or basic functions of myeloid cells.
- MRP-14 and MRP-8 appear dispensable for many critical myeloid cell functions and inflammatory processes.
- These findings suggest a non-essential role for MRP-14 in the studied myeloid cell activities and inflammatory responses.
