**5. Conclusions**

In summary, we have shown that BLT2 played a critical mediating role in the production of G-CSF in steroid-resistant neutrophilic lung airway inflammation. We also found that the blockade of BLT2 suppressed the production of G-CSF, thus alleviating neutrophilic inflammation in the murine model. In support of the mediatory role of BLT2 in the production of G-CSF, the synthesis of its ligands by 12-LO was also shown to be necessary for mediating the production of G-CSF. Together, our results suggest that the 12-LO-BLT2 cascade is critical for the production of G-CSF, thus contributing to the progression of neutrophilic airway inflammation (as summarized in Figure 6). This study was the first to report the mediatory role of BLT2 in the production of G-CSF in neutrophilic asthma. The results provide a new perspective for developing effective therapies for severe neutrophilic asthma.

**Figure 6.** The proposed scheme of the 12-LO-BLT2-G-CSF cascade in LPS/OVA-induced steroidresistant neutrophilic airway inflammation.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/biomedicines10112979/s1, Figure S1: G-CSF is critical for IL-17/IL-1β production in steroid-resistant neutrophilic airway inflammation.; Figure S2: BLT1 has no effect on G-CSF production in the early time point following the challenge.

**Author Contributions:** D.-W.K. and D.P. planned the study, performed the experiments, analyzed data, and wrote the manuscript. J.-H.K. supervised the study and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by a Bio and Medical Technology Development Program grant (2017M3A9D8063317) through the National Research Foundation (NRF) funded by the Ministry of Science, Information and Communication Technologies (ICT) and Future Planning of the Republic of Korea. This work was also supported by a Korea University Grant.

**Institutional Review Board Statement:** All experimental animals used in this study were treated according to guidelines approved by the Institutional Animal Care and Use Committee of Korea University (KU-IACUC), and the experimental protocols were approved by KU-IACUC (Approval no. KU-IACUC-2022-0031).

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
