CXCL1 and CXCL2: Key Regulators of Host Defense Against Phialophora verrucosa

Jiejie Lu,1– 3,* Qi Dong,4,* Ruijun Zhang,4,5 Weiwei Wu,2,6 Huilan Yang1,3 1The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China; 3General Hospital of Southern Theater Command, Guangzhou, Guangdong, People’s Republic of China; 4Department of Dermatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China; 5Department of Dermatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China; 6Department of Dermatology, Affiliated Dermatology Hospital of Hainan Medical University, Haikou, Hainan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiwei Wu, Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China, Email [email protected] Huilan Yang, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China, Email [email protected]: Dematiaceous fungi, such as Phialophora verrucosa (P. verrucosa), cause persistent infections that are difficult to treat. The purpose of this study was to investigate the roles of chemokines CXCL1 and CXCL2 in the innate immune defense against P. verrucosa infections.Methods: A subcutaneous infection model was employed, in which live P. verrucosa conidia were administered into the footpads of wild-type C57BL/6 mice and their Cxcl1 and Cxcl2 knockout (KO) counterparts (equal numbers of male and female mice). The natural course of infection, pathological changes, and immune responses were monitored continuously over four weeks.Results: The current results show that both CXCL1 and CXCL2 deficiencies impair fungal clearance, leading to prolonged infection as evidenced by higher fungal loads and histopathology in Cxcl1/Cxcl2 KO mice at week 4. In Cxcl1 KO mice, increased levels of inflammatory cytokines IFN-γ, G-CSF, and IL-4 were observed, likely compensating for the immunological deficiencies caused by the lack of CXCL1. Conversely, Cxcl2 KO mice exhibited impaired neutrophil infiltration early in infection, accompanied by a significant increase in macrophage infiltration.Conclusion: These findings highlight the critical roles of CXCL1 and CXCL2 in mounting an effective immune response against dematiaceous fungi and suggest their potential as therapeutic targets.Keywords: CXCL1, CXCL2, Phialophora verrucosa, immune response