CXCL3, a member of the C-X-C chemokine subfamily, acts as a potent chemoattractant for neutrophils, orchestrating leukocyte recruitment and migration and triggering an inflammatory response [2]. In the body, it can modulate cellular behaviors via autocrine and paracrine actions, mainly by interacting with its receptor CXCR2, which activates signaling cascades such as ERK/MAPK, AKT, and JAK2/STAT3 [2]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, can be used to study its functions in different biological processes and diseases.

In pancreatic ductal adenocarcinoma (PDAC), CXCL3, highly upregulated in IL-33-stimulated macrophages, is correlated with poor survival [1]. The IL-33-ST2-MYC pathway leads to high CXCL3 production. Activation of CXCR2 by CXCL3 induces a CAF-to-myoCAF transition, with α-SMA upregulated by the CXCL3-CXCR2 signaling, promoting PDAC metastasis [1]. In osteoarthritis, TREM2 deficiency exacerbates joint inflammation, enhancing NF-κB signaling and CXCL3 expression [3]. Knocking down CXCL3 in TREM2-KO mice macrophages suppresses the inflammatory response and promotes chondrocyte proliferation [3].

In summary, CXCL3 is crucial in inflammation and cell-migration-related processes. Through KO/CKO mouse models, its role in diseases like PDAC and osteoarthritis has been revealed. In PDAC, it promotes metastasis, while in osteoarthritis, it is involved in the inflammatory response and chondrocyte regulation, highlighting its significance in understanding these disease mechanisms.

References:

1. Sun, Xiaoting, He, Xingkang, Zhang, Yin, Li, Qi, Cao, Yihai. 2021. Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism. In Gut, 71, 129-147. doi:10.1136/gutjnl-2020-322744. https://pubmed.ncbi.nlm.nih.gov/33568427/

2. Bao, Yuxuan, Tong, Chang, Xiong, Xiangyang. 2024. CXCL3: A key player in tumor microenvironment and inflammatory diseases. In Life sciences, 348, 122691. doi:10.1016/j.lfs.2024.122691. https://pubmed.ncbi.nlm.nih.gov/38714265/

3. Fang, Chao, Zhong, Rui, Lu, Shuai, Zhao, Qichun, Feng, Xinzhe. 2024. TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis. In International journal of biological sciences, 20, 1992-2007. doi:10.7150/ijbs.91519. https://pubmed.ncbi.nlm.nih.gov/38617547/