The Protein Tyrosine Phosphatase CD45 promotes PMN Transepithelial Migration, Antimicrobial Function and Colonic
Abstract:
Polymorphonuclear neutrophils (PMNs) serve as frontline defenders against injury and infection, eliminating pathogens and initiating mucosal tissue repair. However, excessive PMN transepithelial migration (TEpM) contributes to chronic mucosal inflammatory disorders, including inflammatory bowel disease. PMN pro-inflammatory and pro-repair functions are regulated by incompletely defined signaling cascades involving kinases and phosphatases. Here, we determined how the protein tyrosine phosphatase CD45/PTPRC regulates PMN trafficking and effector functions in the gut. Pharmacologic inhibition of CD45 significantly reduced PMN colonic TEpM in vitr o and in vivo and decreased intestinal PMN trafficking was observed in transgenic mice with PMN-specific deletion of CD45 ( MRP8-Cre;Cd45 fl /fl ). Beyond limiting TEpM, CD45 depletion impaired key antimicrobial functions, including degranulation and phagocytosis, indicating broader effects on PMN effector activity. Importantly, recovery from dextran sodium sulfate (DSS)-induced colitis and biopsy-induced colonic wounding was delayed in MRP8-Cre;Cd45 fl /fl mice, linking altered PMN function to defective mucosal healing. Mechanistically, CD45 depletion reduced surface expression of the β2 integrin CD11b/CD18 and inactivated the Src family kinase member Lyn. Together, data highlight a novel CD45-CD11b-Lyn signaling axis that regulates PMN trafficking and effector functions in the intestine and identify CD45 as a promising target for modulating PMN function to promote mucosal tissue repair.
Insights
The protein tyrosine phosphatase CD45 regulates polymorphonuclear neutrophil (PMN) migration and function in the gut. Inhibiting CD45 impairs PMN antimicrobial activity and delays mucosal healing, suggesting CD45 as a therapeutic target.
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Polymorphonuclear neutrophils (PMNs) are crucial for host defense and tissue repair.
- Excessive PMN transepithelial migration (TEpM) exacerbates chronic inflammatory conditions like inflammatory bowel disease.
- Signaling pathways governing PMN functions remain incompletely understood.
Purpose of the Study:
- To investigate the role of protein tyrosine phosphatase CD45 (also known as PTPRC) in regulating PMN trafficking and effector functions within the gastrointestinal tract.
- To elucidate the molecular mechanisms by which CD45 influences PMN behavior in the context of mucosal inflammation and repair.
Main Methods:
- Pharmacological inhibition of CD45.
- Generation and utilization of transgenic mice with PMN-specific deletion of CD45 (MRP8-Cre;Cd45fl/fl).
- Assessment of PMN transepithelial migration (TEpM) in vitro and in vivo.
- Evaluation of PMN antimicrobial functions (degranulation, phagocytosis).
- Analysis of recovery from dextran sodium sulfate (DSS)-induced colitis and biopsy-induced colonic wounding.
- Measurement of surface CD11b/CD18 expression and Lyn kinase activity.
Main Results:
- Pharmacological CD45 inhibition significantly reduced PMN colonic TEpM.
- PMN-specific CD45 deletion in mice led to decreased intestinal PMN trafficking.
- CD45 depletion impaired PMN degranulation and phagocytosis, affecting antimicrobial capabilities.
- Mice lacking CD45 in PMNs exhibited delayed recovery from colitis and colonic wounding.
- CD45 depletion resulted in reduced surface CD11b/CD18 expression and inactivated Lyn kinase.
Conclusions:
- CD45 plays a critical role in regulating PMN trafficking and effector functions in the intestine.
- A novel CD45-CD11b-Lyn signaling axis is identified as crucial for PMN function in the gut.
- Targeting CD45 presents a potential therapeutic strategy for enhancing mucosal tissue repair in inflammatory conditions.
