The induction of mucus production under Nutlin-3 Mdm2 inhibitor bacterial challenges is thus a known innate immune response irrespective of the mCLCA3 status. Interestingly, mCLCA3 independent mucin regulation in airway diseases shows a discrepancy between mice and humans. It was previously hypothesized that upregulation of other members of the murine CLCA family may possibly compensate for the lack of mCLCA3. In addition to mCLCA3, the murine CLCA5, -6, and are potential candidates to drive mucus cell metaplasia in mice. Therefore, we analyzed the lungs regarding a possible compensatory differential regulation of other murine CLCA homologs. mClca1, mClca3, mClca5, and mClca6 were expressed, whereas mClca2, mClca4 and mClca7 were not detected. Of these, only mClca5 was increased during infection, however, independently of genotype. Thus, no differentially regulated and putatively compensatory CLCA member with regard to mucus cell regulation was found, even under challenged conditions which is in line with previous reports. In contrast to the observed reduction in neutrophil infiltration, our pathologic examination failed to reveal differences in lung inflammation or lung lesion expansion between genotypes despite using up-to-date morphometric methods. Infected animals developed an acute, marked, suppurative and necrotizing bronchopneumonia with consolidation and destruction of inflamed areas. Due to this tissue destruction, an exact separation between lung parenchyma and alveolar spaces was impossible and histological quantification of cell types in the two separate compartments that could have confirmed the results of BALF analyses was impossible. Furthermore, no differences in clinical course or lung bacterial loads were observed following infection, indicating that the effect of mCLCA3 on the molecular and subsequent cellular responses had no obvious impact on clinical and pathological outcome at the times investigated. Obviously, additional determinants other than leukocyte number decide on the overall severity of pneumonia and clinical outcome. In conclusion, our data suggest that mCLCA3 modulates the cellular leukocyte recruitment via IL-17 and CXCL-1 in acute S. aureus pneumonia. Lack of mCLCA3 led to a selectively decreased induction of IL-17 and CXCL-8 homologs and decreased numbers of neutrophils and total protein in BALF in S. aureus infected mice. During bacterial infection, no differences were observed in mucin regulation and no other mCLCA family members were differentially regulated. Thus, mCLCA3 seems to have an impact on the early innate immune response via direct or indirect induction of select cytokines during S. aureus infection. Further studies should characterize the specific cytokine pathways and the main target cells activated by mCLCA3 under physiological condition and infection. Prospectively, mCLCA3 may even become a potential therapeutic target for the modulation of inflammation in lung infections.