## 3 Lipid Signalling in Microgravity
### Endocannabinoids  
ECs and the complex EC system have also attracted considerable interest in microgravity-related pathophysiology, especially in the light of their nature as versatile agents involved in adaptation to various environmental and metabolic conditions, immune response and bone remodelling included [14; 77]. During the last two decades, a number of projects have provided insight into the effect of authentic or simulated microgravity on EC signalling and metabolism, as well as on the possible implications of this effect for human health in Space. In particular, we performed two independent missions on board the ISS, namely RESLEM (which was part of the 2011 PromISSe mission organized by ESA), and SERISM (which was performed in 2017 in the frame of the Italian Space Agency VITA mission). These were among the few studies proving that the EC system is indeed one of the targets through which weightlessness triggers immune alterations and loss of bone density [13; 19; 20; 93]. The data obtained from the RESLEM experiment showed that, under authentic microgravity, human PBMCs undergo a time-dependent re-modulation of the two main AEA metabolic enzymes. After 48 h on the ISS, a down-regulation of FAAH and a concomitant up-regulation of NAPE-PLDwere observed, both at mRNA and protein levels, suggestive of enhanced production of AEA as a likely adaptive response of immune cells to prolonged microgravity [13]. Incidentally, LOXs can also control endogenous AEA content by producing AEA hydroperoxides that competitively inhibit FAAH [12]. As reported above, microgravity also induces an early increase of 5-LOX activity in PBMCs (and hence an inhibition of FAAH), further supporting the concept of increased AEA content as a crucial response and adaptation of PBMCs to microgravity [12]. Interestingly, the effect of microgravity on EC production and immune response is also supported by other recent studies, such as the one stemming from the IMMUNO mission, which assessed the immune functions and stress levels of ISS crew members undergoing long-term Space flight [77]. This project confirmed a significant and persistent increase of EC levels (especially AEA) in blood, also associated with altered immune cell repertoire and functionality characterized by enhanced numbers of neutrophils, NK cells, B cells and monocytes, reduced amounts of Treg lymphocytes, as well as by an overproduction of pro-inflammatory cytokines (e.g., TNF and IL-1\(\beta\)) and a reduction of the anti-inflammatory ones (TGF-\(\beta\), and IL-10) [14]. Interestingly, increased EC blood levels were also reported by other studies, where microgravity was achieved through parabolic flights [19; 20]. In this paradigm, human subjects were exposed to low-duration (\(\sim\) 20 s) weightlessness, suggesting that ECs are not only involved in long-term adaptation to Space--where they might act on processes like immune response independently of stress sources--but also as stress-induced adaptive agents that participate in responding to immediate environmental modifications. Interestingly, only individuals who did not experience flight-related motion sickness showed enhanced EC levels, while those experiencing kinetosis did not show any significant change [19; 20]. Again, these findings point to a role of ECs in the swift adaptation to altered gravity. It should be recalled that ECs are also involved in bone metabolism [63; 64]. This issue was addressed by the SERiSM project, whereby human blood-derived stem cells (hBDSCs) were driven towards osteogenic differentiation under authentic microgravity on board the ISS [15; 93]. In this cellular model, possible alterations of the EC system were also interrogated [16; 93]. Our study demonstrated that microgravity modulates the expression of the two main cannabinoid receptors of hBDSCs, eliciting an up-regulation of CB\({}_{1}\) and a down-regulation of CB\({}_{2}\)[80].