Human CXCR1 knock-in mice infer functional expression of a murine ortholog
Farnaz Fahimi1, Md Jahangir Alam2, Caroline Ang3
1Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
Abstract:
Targeting CXCR1 and CXCR2 chemokine receptors to block neutrophil migration to sites of inflammation is a promising therapeutic approach for various inflammatory and autoimmune diseases. However, assessing the translational potential of such therapies using mouse models is challenging due to the unclear expression of CXCR1 at the protein level. Although CXCR2 has been well characterized in both mice and humans, the protein-level expression of CXCR1 in mice (mCXCR1) remains controversial. To address this issue, we generated a novel human CXCR1 knock-in (hCXCR1 KI) mouse model in which the transgene is under the control of the native mouse promoter and regulatory elements. Using an anti-human CXCR1 monoclonal antibody (anti-hCXCR1 monoclonal antibody), we found that hCXCR1 was highly expressed on neutrophils in the hCXCR1 KI mice, comparable to levels observed in human neutrophils. This successful expression of hCXCR1 in this mouse model suggests that functional mCXCR1 likely exists. To investigate the functional role of CXCR1, we investigated how antagonizing this receptor using anti-hCXCR1 monoclonal antibody in the arthritis model would affect disease outcomes. Antibody treatment significantly alleviated all signs of joint inflammation. In summary, our newly generated hCXCR1 KI transgenic mice provide a valuable tool to investigate the therapeutic efficacy of small molecules or monoclonal antibodies that antagonize this receptor in neutrophil-mediated pathologies.
Insights
Researchers developed a human CXCR1 knock-in mouse model to study inflammatory diseases. This model successfully expresses human CXCR1 on neutrophils, validating its use for testing CXCR1-targeting therapies against autoimmune conditions.
Area of Science:
- Immunology
- Pharmacology
- Genetics
Background:
- Targeting CXCR1 and CXCR2 receptors can block neutrophil migration in inflammatory diseases.
- Assessing CXCR1 therapies in mice is difficult due to unclear mouse CXCR1 (mCXCR1) protein expression.
- A novel human CXCR1 knock-in (hCXCR1 KI) mouse model was created to overcome this challenge.
Purpose of the Study:
- To generate and validate a human CXCR1 knock-in (hCXCR1 KI) mouse model.
- To investigate the functional role of CXCR1 in an arthritis model.
- To assess the therapeutic potential of targeting CXCR1 in neutrophil-mediated pathologies.
Main Methods:
- Generated a human CXCR1 knock-in (hCXCR1 KI) mouse model using native mouse promoter and regulatory elements.
- Utilized an anti-human CXCR1 monoclonal antibody to detect hCXCR1 expression on neutrophils.
- Administered anti-hCXCR1 monoclonal antibody in a mouse arthritis model.
Main Results:
- hCXCR1 was highly expressed on neutrophils in hCXCR1 KI mice, comparable to human neutrophils.
- The successful expression of hCXCR1 suggests functional mCXCR1 likely exists.
- Antibody treatment significantly reduced joint inflammation in the arthritis model.
Conclusions:
- The novel hCXCR1 KI mouse model is a valuable tool for studying CXCR1 function.
- This model facilitates the investigation of therapeutic strategies targeting CXCR1 in neutrophil-driven diseases.
- The findings support the potential of CXCR1 antagonism for treating inflammatory and autoimmune diseases.
