This suggests that acrolein could mediate part, but not all, of CSC’s negative effects in vitro and in vivo. As discussed previously, M1 microglia have detrimental effects during MS/EAE. However, it does not mean that pro-inflammatory mediators like M1 microglia and Th1 cells only contribute adversely to MS/EAE. Controlled microglial activation and T cell infiltration promote optic nerve recovery from injury. Appropriate amounts of M1 differentiation have been shown to promote neurogenesis and oligogenesis, whereas excessive activation is inhibitory. Rebalancing the pro-inflammatory and anti-inflammatory ICG-001 factors is critical for disease progression and recovery, which is supported by our results showing the opposite courses of disease development of CSC- and nicotine-treated EAE animals. Results from our lab and others suggest that nicotine could be a good candidate as an inflammatory regulator since it suppresses pro-inflammatory differentiation of microglia and T cells without affecting cell viability. We also demonstrated that nicotine administration significantly limits exacerbation and disease severity in established EAE. This is the first study that provides evidence to support the proposal that nicotine could be used as a therapy for on-going MS. The therapeutic effect of nicotine transdermal patches on MS/EAE is currently under investigation. However, some considerations may apply to the proposal to use nicotine. Although nicotine ameliorated symptoms of EAE in our study here, it has been associated with inflammation in the respiratory system and cancer. The potential side effects of nicotine patches will need to be evaluated carefully. Recent studies by Odoardi et al. have demonstrated that the lung contributes to the T cell activation and migration that are required for MS/EAE initiation. This may explain why lung infections are associated with MS progression. Importantly, there are many components in cigarette smoke that can modify the physiology of the lung but have not yet been shown to have direct effects on the CNS. It is possible that one of the pathways through which CSC affects EAE is through changing the inflammatory environment in the lungs and thus altering T cell differentiation. However, the respiratory system was not included in our study because we used osmotic pumps to deliver the CSC systemically into mice and thus the CSC components did not directly interact with the respiratory system. As this method is not an accurate representation of the delivery of cigarette smoke in human MS patients, to better model the effects of CSC on MS/EAE, a method that subjects mice directly exposed to cigarette smoke, such as an inhalation chamber, may need to be employed. Furthermore, the vertical flux of carbon has been assumed to be equal to new production over the appropriate time and space scales. The occurrence of nitrification in the photic zone complicates these paradigms by providing a regenerated source of NO32.