## 9 Inhibition of Dendritic Cells Function to Prevent Renal Injury  
In 1999, [PERSON] et al. investigated for the first time the influence of N-acetyl-l-cysteine (NAC), an antioxidant molecule, on human DCs, evaluating NF-\(\kappa\)B activity, cytokine production, and expression of co-stimulators both at the basal state and after activation by either LPS or CD40 engagement. The authors reported several NAC-mediated consequences on DCs: (i) Inhibition of both constitutive and LPS-induced NF-\(\kappa\)B activation; (ii) down-regulation of cytokines production and DCs-specific surface markers expression (i.e., HLA-DR, CD86, and CD40) both at the basal condition and after activation with LPS; (iii) inhibition of DCs responses following CD40 engagement. All these findings revealed NAC was able to indirectly inhibit the primary T-cell responses through its immunosuppressive action on DCs, offering a potential strategy to prevent undesirable immune responses [49]. In 2006, NAC capability to inhibit DCs was further studied by [PERSON] et al. in mice receiving renal IR, mimicking human AKI. Animals have been divided into two groups, each one receiving a different concentration of NAC before surgery, and renal function, acute tubular necrosis and immune-phenotyping of infiltrating cells have been evaluated. Interestingly, mice treated with higher dose of NAC had lower serum creatinine levels and lower acute tubular necrosis with reduced renal DCs infiltration, showing NAC pretreatment was beneficial in limiting IR-induced damage [50]. A similar effect in preventing IRI was described by [PERSON] et al., when testing a selective agonist of adenosine 2A (A\({}_{\text{2A}}\)) [46; 51]. A\({}_{\text{2A}}\) is an important anti-inflammatory molecule released during tissue inflammation, whose concentration can increase more than six-fold after only two minutes of ischemia. The innate immune cells have several types of adenosine-surface receptors (A\({}_{\text{2A}}\)-Ars) able to modulate the cellular responses inhibiting inflammation [52]. [PERSON]'s group investigated whether selective activation of A\({}_{\text{2A}}\)-Ars was able to reduce renal IRI, testing the A\({}_{\text{2A}}\) agonist DWH-146e in rodent models of ischemic AKI. These models were chosen because of their well-established processes of reperfusion on the inflammatory pathways [46; 51; 53]. Results showed that DWH-146e was able to protect the kidney from IRI, inducing a reduction of plasma creatinine, even when the compound was administered during reperfusion period [49]. As DWH-146e was described to preserve both renal function and histology [46], additional studies deepened insight into the possible mechanisms involved in A2 AR-agonist-mediated protection. Another study showed that DWH-146e administration reduced renal neutrophil accumulation, oxidative activity, and adhesion in mice subjected to IR 34. Additional works focused on the direct effect that another A\({}_{2\text{A}}\)-ARs agonists (ATL313) had in modulating DCs signaling and activation. Notably, mice with A\({}_{2\text{A}}\)-Ars-deficient DCs did not respond to ATL313 agonists and had worse kidney injury. On the contrary, administration of DCs treated ex vivo by ATL313 ameliorated kidney IRI of wild-type mice owing to the direct suppression of NKT cell activation. Of note, the fact that DCs could induce both immunity and tolerance according to the microenvironment condition was well established [52], however, the fact that A\({}_{2\text{A}}\)-ARs agonist-mediated tolerance was the result of direct suppression of other immune cells function by DCs was a novel finding. Further progress in understanding the side effects associated with DCs suppression has been made by [PERSON] et al., using a graft-versus-host disease model.