## 4 Discussion  
The present systematic review highlights that caryophyllane sesquiterpenes possess immunomodulatory properties which can contribute to their beneficial effects in various pathological conditions. Among the caryophyllane sesquiterpenes, \(\beta\)-caryophyllene is the most studied compound in both in vitro and in vivo models; the modulation of macrophage function in inflammatory conditions has been mainly characterized, although the changes in the recruitment of other immune cells, including lymphocytes, neutrophlies, and eosinophils in other pathologies, such as tumors and allergic diseases, have been highlighted too. Similar effects on macrophage function have been found for \(\beta\)-caryophyllene oxide, albeit highlighted in just one study [33]. Considering the structural similarity with \(\beta\)-caryophyllene and the recently highlighted ability to modulate CB2 receptor expression [2], it is conceivable that it can act like the lead compound, thus suggesting the need for further investigation. As regards \(\alpha\)-humulene, though it is poorly studied, the available evidence highlighted its ability to counteract the LPS-induced inflammatory response of macrophages in vitro at high concentration [32], suggesting a weaker potency compared to \(\beta\)-caryophyllene and \(\beta\)-caryophyllene oxide. Conversely, it was able to modulate immune response related to allergic diseases (e.g., decreased immune cell infiltration, inhibition of the Nf-kB and AP-1 pathways, and the release of asthma-related modulators, such as CCL11, LTB4 and IL-5) in mice, as displayed in Figure 3, despite a null effect of \(\beta\)-caryophyllene [48]. This evidence suggests a possible role of \(\alpha\)-humulene as a novel strategy to treat asthma and allergic diseases and deserves to be further investigated. The in vitro immunomodulatory effects of \(\beta\)-caryophyllene were usually studied in the concentration range of 0.25-50 \(\upmu\)M, while at higher concentrations the substance seemed to affect cell viability, which was probably due to a stimulation of the pro-apoptotic pathways [30]. Interestingly, \(\beta\)-caryophyllene exhibited cytoprotective and anti-inflammatory properties against different stressors, including LPS and A\(\beta_{1-42}\) peptide, and in different in vitro models of macrophages, microglial cells, monocytes, and lymphocytes, likely ascribed to the activation of CB2 receptors. In particular, blocking the microglia activation into the M1 inflammatory phenotype has been associated with the neuroprotective effects of \(\beta\)-caryophyllene, which have been further confirmed in animal models of Parkinson's disease and multiple sclerosis. [PERSON] et al. [40] hypothesized that the cytoprotective effects of \(\beta\)-caryophyllene in microglial cells occurred via activation of the CB2 and PPAR\(\gamma\) receptors and through the involvement of ceramides. Indeed, after activation of the CB2 receptor by the sesquiterpene, the CB2-activated \(\beta\gamma\)-subunit can stimulate sphingomyelinase (SMase) activity, responsible for producing ceramides, which in turn activate the PPAR-\(\gamma\) receptor [49], leading to anti-inflammatory and antioxidant effects [40]. As a consequence, PPAR\(\gamma\) can control the inflammatory response through the inhibition of Nf-kB and other inflammatory pathways and the activation of antioxidant degrees, such as Nrf/HO-1 signaling [40]. Accordingly, decreased levels of pro-inflammatory factors, such as TNF-\(\alpha\), IL-\(\beta\), IL-10, NO and PGE2, and oxidative stress parameters (e.g., ROS level reduction), along with an inhibition of iNOS and COX-2 enzymes and a restoring of antioxidant defenses (i.e., GSH) has been found in microglial cells after treatment with \(\beta\)-caryophyllene [40, 42, 44, 45].