Nrf2 downregulates zymosan-induced neutrophil activation and modulates migration

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Polymorphonuclear neutrophils (PMNs) are critical immune cells requiring tight regulation to prevent tissue damage.
• The transcription factor Nrf2 (Nuclear factor erythroid-derived 2-like 2) is known to regulate oxidative stress and inflammation in other cell types.
• The specific role of Nrf2 in PMN biology remained largely unexplored.

Purpose of the Study:

• To investigate the protective function of Nrf2 in key PMN activities.
• To elucidate Nrf2's involvement in oxidative burst, netosis, migration, cytokine production, and phagocytosis.
• To assess Nrf2's role in PMN responses, particularly in the context of zymosan stimulation.

Main Methods:

• Utilized Nrf2 knockout (KO) mice to study PMN functions.
• Stimulated PMNs with zymosan and measured oxidative burst, gene transcription, and migration.
• Assessed the impact of sulforaphane on Nrf2 hyperexpression and PMN activity.

Main Results:

• Zymosan induced Nrf2 accumulation in PMNs, upregulating target genes like Hmox-1, Nqo1, and Cat.
• Nrf2 significantly decreased zymosan-induced PMN oxidative burst and downregulated proinflammatory cytokine (Tnfα, Ccl3, Cxcl2) gene transcription.
• Nrf2 deficiency impaired spontaneous and CXCL2/CXCL12-induced PMN migration, while phagocytosis remained unaffected.

Conclusions:

• Nrf2 plays a protective role in PMN biology by downregulating excessive activation, particularly in response to zymosan.
• Nrf2 is essential for optimal PMN migration, suggesting a broader regulatory function in immune cell trafficking.
• These findings highlight Nrf2 as a key regulator of PMN function and a potential therapeutic target for inflammatory conditions.