Role of the cytoskeleton in neutrophil activation and inflammation

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* *** ** ** *****The*cytoskeleton is a dynamic structure composed of numerous proteins involved in*different cellular functions. This is particularly true for human*polymorphonuclear neutrophils (PMNs), the most abundant leukocytes in the blood*and key player cells in inflammation. Despite this, the role of cytoskeletal*proteins (CKp) in inflammation remains unclear. Inflammation is a normal immune*response against a variety of assaults including not only pathogens, but also*injuries, drugs, chemicals, and, more recently, nanoparticles (NPs), that is transient and resolved under normal*circumstances. However, when deregulation occurs, inflammation can persist,*leading to undesired effects, including cell death, tissue damage and diseases.*Because the resolution of inflammation largely occurs by the elimination of*apoptotic PMNs by professional phagocytes (efferocytosis),*it is important to understand the mode of action of PMN activators and to*elucidate how they alter the cytoskeleton. Recently, we have shown that some*CKp are expressed on the cell surface of apoptotic PMNs, including vimentin,*lamin B, ezrin, moesin and more recently, α-fodrin, but their role remains*elusive. As our research program evolves over time, we have recently*demonstrated that some NPs are new agents that can also induce human PMN*apoptosis, cytoskeletal rearrangement as well as inflammation. For example,*gold NPs were found to induce apoptosis, endoplasmic reticulum stress events*and cleavage of some CKp in human PMNs, but did not increase their cell surface*expression during apoptosis. This indicates that cell surface expression of CKp*could even be a context-dependent phenomenon according to the proapoptotic agent*tested. However, this remains to be determined. * ***In the*present short-term objectives, we will determine:***i) if*other CKp are degraded during PMN apoptosis and expressed at the cell surface*of apoptotic PMNs.***ii) if*the cell surface CKp are involved in efferocytosis.***iii) if a*given CKp is involved in PMN functions *** *The long-term objectives are: i) to catalogue which CKp are expressed at the cell surface of*apoptotic PMNs; ii) to*determine the importance of the cytoskeleton during efferocytosis and other PMN*functions; and iii) to guide*future studies on specific CKp and their roles during PMN activation and*inflammation. ***Understanding*the molecular and cell biology events occurring during cytoskeleton*reorganisation in human PMNs are fundamental for better understanding not only*the biology of these cells, but will also increase our knowledge on general*inflammation. In the very long term, it is highly predictable that our results*will allow the generation of knockout mice for a given CKp. This will represent*powerful tools for the scientific community and will help to better increase*our knowledge on the importance of the cytoskeleton and CKp in leukocyte*cellular physiology and inflammation. ******