Challenging the Leukocyte‐Centric Model of Innate Immunity: The Emerging Role of Structural Cells in Immune Defense

Abstract

Innate immunity has long been viewed as the domain of circulating mobile immune cells orchestrating defense through systemic responses. However, this model cannot explain why some tissues can provide hyperlocal and confined protection to specific microenvironments that precede systemic leukocyte recruitment. A recent integrative systems‐level analysis identified 46 structural cell types from blood vessels to neurons that actively sense danger and coordinate immune responses alongside traditional immune cells. These cells, previously dismissed as passive barriers, integrate biochemical, mechanical, and immune signals, sense danger‐associated pattern recognition receptors, and execute immune effector functions, including cytokine production and trained immunity. The discovery reshapes understanding of immunity as a distributed network where tissue‐resident cells act as primary responders, not bystanders. This insight opens new therapeutic possibilities: instead of globally suppressing immunity to control inflammation, future therapeutics could enable targeted modulation of intrinsic immune programs of specific cell types in damaged tissues rather than indiscriminate systemic suppression, offering novel approaches for precision medicine.