Indeed we observed some important modifications in the activ

Indeed, we observed some important modifications in the activation of APC from CS-exposed mice, but also in not conventional lymphocytes. Major cellular sources of IL-17 and IL-22, described as NK, NKT, ILC in mice and humans (Colonna, 2009; Liang et al., 2006; Sonnenberg et al., 2012; Van Maele et al., 2010), failed to produce higher levels of Th17 cytokines in response to Sp in CS-exposed mice whereas only the production of IL-22 was altered in conventional T cells. According to the implication of such methylphenidate hcl in the protection against Sp (Marques et al., 2012; Clement et al., 2008; Van Maele et al., 2010), this suggest that this defect might be an important determinant of bacterial susceptibility during COPD. In contrast, the activation of conventional T cells, MAIT and γδT cells was not clearly modified during COPD. The defective activation of conventional T cells and some innate populations could be explained by the alteration of pulmonary APC, as previously reported in CS-exposed mice (Pichavant et al., 2014; Kroening et al., 2008). Indeed expression of pro-Th17 cytokines, such as IL-1β and IL-23 (Mucida and Salek-Ardakani, 2009), was decreased both in lung AM and DC from infected CS-exposed mice. IL-23 plays a key role in the clearance of the bacteria and the production of Th17 cytokines by ILC (Van Maele et al., 2014). IL-23 is also needed for IL-17 expression by others immune cells like NKT and γδ T-cells (Clement et al., 2008). Therefore, APC from CS-exposed mice cannot correctly educate the T cells and other innate cells to respond to Sp. Such a defective production of IL-1β and IL-23 was also observed in COPD patients in response to Sp. (Kroening et al., 2008).Altogether, during COPD, the reduced production of IL-17 and IL-22 by conventional T cells and other innate cells might result from a deficient IL-1β and IL-23 synthesis by DC in response to Sp. Functionally, IL-17 and IL-22 have been reported as essential factors in anti-bacterial defenses. During infection, the early production of IL-22 by innate immune cells is crucial for host protective immunity (Aujla et al., 2008; Graham et al., 2011; Zheng et al., 2008) including a role in chemotaxis and tissue repair (Wolk et al., 2004; Zheng et al., 2008; Eyerich et al., 2010; Kolls et al., 2008; Sonnenberg et al., 2010; Witte et al., 2010). It has been recently shown that IL-17A is required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke although the role of IL-22 was not evaluated (Roos et al., 2015). Moreover, IL-17 and IL-22 induced the production of anti-microbial peptides (including β-defensins, S100A7-9, Reg3β and Reg3γ) important in the containment of pathogens (Zheng et al., 2008; Kolls et al., 2008; Sonnenberg et al., 2010; Cash et al., 2006). In our report, the defective production of IL-22 in CS-exposed mice to Sp was not associated to an impaired production of these antimicrobial peptides as previously reported in COPD patients (Pace et al., 2012). Nevertheless, opposite results have been reported suggesting that the levels of antimicrobial peptide expression were insufficient to control the higher bacterial load both in COPD patients and mice. We can also suspect that bacterial susceptibility in infected CS-exposed mice was not solely related with the defective production of cathelicidin, an IL-22 independent peptide involved in defense against Sp (Felgentreff et al., 2006). Interestingly, local administration of rmIL-22 amplified β-defensin levels in the lungs and a competent immune response, allowing Sp clearance in CS-exposed mice. No impact on neutrophil influx was observed in infected CS-exposed mice, suggesting that the effect of this cytokine is mostly related with cell priming to efficiently kill the bacteria and/or the release of anti-microbial peptides. In these settings, the preventive role of IL-22 on lung injury is potentially linked to its complementary action on the induction of antimicrobial peptides, the activation of immune cells (including neutrophils) and in the maintenance of the epithelial barrier (Kumar et al., 2013). In infected CS-exposed animals, treatment with rmIL-22 results in an efficient resolution and to the preservation of lung tissue after infection, as previously reported in inflammatory models (Liu et al., 2009). The balance between IL-17 and/or IL-22 expression has been found to contribute to either the pro-inflammatory or tissue-protective phases of lung defense, depending on the context (Liang et al., 2006; Eyerich et al., 2010; Sonnenberg et al., 2010). In our model, a protective role for IL-17 cannot be excluded (Lu et al., 2008), since the production of IL-17 was also defective in CS-exposed mice and patients in response to Sp. However, IL-17 is implicated in COPD pathogenesis. During COPD exacerbation, this cytokine has no effect on lung bacterial load and promotes the neutrophil recruitment which is potentially deleterious (Roos et al., 2015).