Cxcr1, also known as C-X-C chemokine receptor 1, is a crucial chemokine receptor mainly activated by interleukin 8 (IL-8 or CXCL8) [2]. It is expressed in various cells like leukocytes, fibroblasts, endothelial cells, and smooth muscle cells. Cxcr1, along with Cxcr2, is involved in the CXCL8-CXCR1/2 pathway, which is essential for the activation and trafficking of inflammatory mediators, as well as tumor progression and metastasis [1]. This pathway plays a role in multiple diseases including cancer, chronic obstructive pulmonary diseases (COPD), asthma, and cystic fibrosis [1].

Knockout of Cxcr1 inhibits the release of reactive oxygen species (ROS) from neutrophils and synergistically enhances the ability of endothelial cells to eliminate ROS, alleviating hyperoxia-induced lung injury. This is achieved through promoting glutamine metabolism and leading to reduced glutathione by upregulating the expression of malic enzyme 1 [3]. In addition, in EGFR-mutant non-small-cell lung cancer, resistant samples have a markedly enriched CXCR1+ neutrophil infiltration compared to pretreatment samples, and CXCR1+ neutrophils result in resistance to third-generation EGFR-TKI via activating the TNF-α/NF-κB signaling pathway in tumor cells [4]. Also, CXCR1/2 inhibition in cancer alters neutrophil function by blocking the polarization of transcriptional programs toward immune suppressive phenotypes, rather than reducing neutrophil recruitment into the tumor [5].

In conclusion, Cxcr1 is a key receptor in the CXCL8-CXCR1/2 pathway, playing significant roles in inflammation-related diseases and cancer. Studies on Cxcr1 knockout models have revealed its importance in processes such as redox balance in hyperoxia-induced lung injury, and in the context of cancer, in influencing treatment resistance and neutrophil-mediated immune suppression. These findings contribute to our understanding of disease mechanisms and potential therapeutic strategies.

References:

1. Ha, Helen, Debnath, Bikash, Neamati, Nouri. 2017. Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases. In Theranostics, 7, 1543-1588. doi:10.7150/thno.15625. https://pubmed.ncbi.nlm.nih.gov/28529637/

2. Dhayni, Kawthar, Zibara, Kazem, Issa, Hawra, Kamel, Saïd, Bennis, Youssef. 2022. Targeting CXCR1 and CXCR2 receptors in cardiovascular diseases. In Pharmacology & therapeutics, 237, 108257. doi:10.1016/j.pharmthera.2022.108257. https://pubmed.ncbi.nlm.nih.gov/35908611/

3. Qin, Hao, Zhuang, Wei, Liu, Xiucheng, Chen, Chang, Zhang, Hao. 2023. Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism. In Cell reports, 42, 112745. doi:10.1016/j.celrep.2023.112745. https://pubmed.ncbi.nlm.nih.gov/37405911/

4. Wang, Haowei, Xiong, Anwen, Chen, Xiaoxia, Hou, Likun, Jiang, Tao. 2024. CXCR1+ neutrophil infiltration orchestrates response to third-generation EGFR-TKI in EGFR mutant non-small-cell lung cancer. In Signal transduction and targeted therapy, 9, 342. doi:10.1038/s41392-024-02045-2. https://pubmed.ncbi.nlm.nih.gov/39638994/

5. Kwak, Jeff W, Nguyen, Helena Q, Camai, Alex, Randolph, Timothy W, Houghton, A McGarry. 2024. CXCR1/2 antagonism inhibits neutrophil function and not recruitment in cancer. In Oncoimmunology, 13, 2384674. doi:10.1080/2162402X.2024.2384674. https://pubmed.ncbi.nlm.nih.gov/39076249/