The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages

Area of Science:

• Cell Biology
• Immunology
• Pharmacology

Background:

• Polymyxin B (PMB) is vital against multidrug-resistant bacteria like MDRP.
• PMB's clinical use is limited by nephrotoxicity and neurotoxicity, linked to its cytotoxicity.
• Mechanisms of PMB-induced cytotoxicity remain unclear.

Purpose of the Study:

• To investigate the cytotoxic mechanisms of Polymyxin B (PMB) in different cell types.
• To elucidate the role of macrophages in PMB-induced toxicity.
• To identify molecular pathways involved in PMB's adverse effects.

Main Methods:

• Comparative cytotoxicity assays of PMB on macrophages, fibroblasts, and proximal tubule (PT) cells.
• Analysis of high mobility group box 1 (HMGB1) release following PMB exposure.
• Assessment of NLRP3 inflammasome activation and IL-1β release in PMB-treated macrophages.
• Investigation of gasdermin D (GSDMD) involvement in PMB-induced cell death.

Main Results:

• Macrophages exhibit heightened sensitivity to PMB compared to other cell types.
• PMB induces macrophage necrosis, leading to passive release of HMGB1.
• PMB stimulates the NLRP3 inflammasome pathway in macrophages, promoting IL-1β release independently of GSDMD.
• This suggests PMB causes plasma membrane rupture during necrosis.

Conclusions:

• PMB-induced macrophage necrosis and subsequent release of HMGB1 and IL-1β may drive excessive inflammation.
• These inflammatory mediators released from macrophages are implicated in PMB's nephrotoxicity and neurotoxicity.
• This study offers new insights into the mechanisms underlying Polymyxin B's adverse organ toxicity.