We believe that by proposing a site of initiation for the final common pathway, future research may lead to an unifying model including non-substance dependent addictions to gain further mechanistic insight, and propose rational therapies. Neutrophils are the most abundant white blood cell in the body, playing an essential role in the destruction of invading bacterial and fungal pathogens. They are rapidly recruited to sites of injury, where they extravasate into the tissues and destroy the pathogen via several mechanisms, including phagocytosis, and the release of antimicrobial substances. Activated neutrophils also release a plethora of proinflammatory mediators such as IL-8, IP-10 and leukotriene B4, recruiting and activating further inflammatory cells, thus enhancing the inflammatory response. Neutrophil functions are limited by a process of neutrophil senescence, which renders neutrophils unable to respond to chemoattractants, carry out respiratory burst, or to degranulate. Senescence is accompanied by an upregulation of CXCR4 on the neutrophil PD325901 surface and a corresponding increase in ability to migrate to SDF-1 ; these changes home neutrophils back to the bone marrow where they undergo apoptosis. In parallel, aged neutrophils can also undergo spontaneous apoptosis, with a half-life of less than 8 hours. This is followed by their subsequent removal by phagocytic cells such as macrophages, a mechanism to prevent unwanted inflammation and tissue damage. GMCSF is a cytokine with multiple effects on neutrophil maturation, and on the function of inflammatory neutrophils. The actions of GMCSF include delaying neutrophil senescence, in part by the suppression of neutrophil apoptosis. Neutrophil apoptosis is thought to be a major factor in the functional senescence of neutrophils, and the role of changes in protein expression caused by microRNAs have not to date been investigated. The mechanisms of the regulation of neutrophil senescence have not been well characterised. It is now well known, however, that neutrophil lifespan is exquisitely regulated both positively and negatively by interaction with environmental cues such as bacterial products or cytokines. Rates of neutrophil apoptosis can be increased by the ingestion of pathogens such as E.coli, and through ligation of cell surface receptors such as Fas and TRAIL-R2 . Conversely, the lifespan of a neutrophil can be extended through stimulation by inflammatory mediators such as GMCSF and TNFa, with associated functional longevity of pro-inflammatory and anti-microbial functions. New protein translation is important in maintaining neutrophil functional viability: blocking either translation or transcription increases the rate of neutrophil apoptosis. We therefore hypothesised that dynamic changes in microRNA levels within neutrophils might regulate proteins instrumental in determining neutrophil functional longevity.