**Conflict of interest**

*Neutrophils*

Studies concerning the modulation of neutrophil activity by cannabinoids during infections are mostly addressed to experimental bacterial infection as sepsis model. Neutrophil activity during experimental sepsis is well characterized in studies *in vivo* (to review [97–99]). By using LPS sepsis model, Smith and coworkers showed that treatment with cannabinoid receptor agonists reduced the migration of neutrophils in the peritoneal cavity by inhibiting neutrophil chemoattractant production [59]. The authors conclude that CB2 was responsible for impairing neutrophil migration. In accordance, studies performed in CB2-deficient mice submitted to sepsis induced by cecal ligation and puncture showed increased production of neutrophil chemotactic chemokines and increased numbers of neutrophil in the bone marrow and lung tissue. Interestingly, despite the increase in neutrophil numbers, neutrophils from CB2-deficient mice were not able to activate the MAPK pathway neither control bacterial load [57, 100]. Furthermore, in mycobacteria model of infection, it was observed that CB2 agonism impairs neutrophil adhesion

to endothelial cells probably by inhibiting actin polymerization [83].

endocannabinoid system, especially the CB2 pathway, during infections.

diseases such as arthritis and infection-induced acute lung injury.

An increasing amount of data concerning the immunoregulatory role of cannabinoids, especially the CB2 agonists, has been raising the interest in developing new therapeutic strategies for inflammatory diseases. It is already known that the mechanism of action of well-established anti-inflammatory drugs, like paracetamol, depends on the activation of the endocannabinoid system [29]. However, despite all studies showing that cannabinoids can modulate neutrophil biology, there is a long way to go to achieve cannabinoid-based drugs to treat neutrophil-dependent

The authors express their gratitude to Luana Barbosa Correa at the Laboratory of Applied Pharmacology (Farmanguinhos, FIOCRUZ) for her support in drawing **Figure 2**. This work was supported by grants from the Brazilian Council for Scientific and Technological Development (CNPq), Carlos Chagas Filho, Rio de Janeiro State Research Supporting Foundation (FAPERJ), and Oswaldo Cruz

There are few and controverting data concerning CB1 effects on neutrophils during infection. Leite-Avalca and coworkers showed that CB1 antagonist given to mice submitted to CLP increased the survival rate but not change neutrophil accumulation in the peritoneal cavity [101]. Nevertheless, Kianian and coworkers showed that antagonism of CB1 reduced the adhesion of leukocytes to intestinal submucosal venules [102]. It is noteworthy that in the sepsis model, the activation of CB1 increases the systemic arterial pressure and the flow and decreases the arterial oxygenation; however, it decreases the inflammatory cytokine production [103, 104]. In such a way, an indirect effect of CB1 on leukocyte behavior during sepsis cannot be ruled out. The results regarding the immunomodulatory effects of cannabinoids in infection are in accordance with the host-directed therapy approach that aims to activate protective responses against microbes in addition to antimicrobial therapy [105]. However, it should be mentioned that antibiotics perturb gut microflora, which could result in the endocannabinoid system unbalance and, thus, in neuropsychiatric disorders [29]. Indeed, further studies are necessary to propose to activate the

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**4. Conclusion**

**Acknowledgements**

Foundation (FIOCRUZ).

The authors declare no conflicts of interest.
