An islet-resident macrophage antioxidant program preserves β cell physiology.

Area of Science:

• Immunology
• Endocrinology
• Cell Biology

Background:

• Pancreatic islet-resident macrophages (IRMs) are activated but their origins, diversity, and functions are unclear.
• Understanding IRM roles is vital for islet development, remodeling, and metabolic health.

Purpose of the Study:

• To investigate the origin, heterogeneity, and functional significance of pancreatic IRMs.
• To identify molecular mechanisms underlying IRM function in maintaining islet homeostasis.

Main Methods:

• Utilized complementary fate-mapping systems in adult mice.
• Performed integrated single-cell RNA sequencing on mouse and human islets.
• Analyzed transcriptional programs, including SLC7A11 expression, in IRM subsets.

Main Results:

• Approximately half of adult mouse IRMs derive from circulating monocytes with low turnover.
• Identified four distinct IRM states characterized by inflammatory and metabolic activation.
• SLC7A11-expressing IRMs exhibit enhanced antioxidant defense and preserve beta cell function.

Conclusions:

• IRMs are specialized immune sentinels in the pancreas, originating partly from monocytes.
• SLC7A11 is a key macrophage-intrinsic factor protecting against oxidative stress in islets.
• These findings have implications for islet resilience and managing metabolic diseases.