A New Paradigm: 46 Structural Cell Types Function as Environment‐Supporting Innate Immune Cells, With Endothelial and Vascular Smooth Muscle Cells as Key Prototypes

ABSTRACT The scope, organization, and biological significance of innate immune functions across structural cell types remain poorly defined. To address these fundamental knowledge gaps, we analyzed experimental data of transcriptomes generated by our group and others. Our findings demonstrated the following: (1) The 46 identified innate immune structural cell types exhibit a dual functional identity: under physiological conditions, they maintain tissue architecture and organ‐specific homeostasis, whereas under immune stress, they transition into environment‐supporting innate immune cells that actively participate in pathogen/damage‐associated molecular pattern (PAMP/DAMP) sensing and immune effector responses. (2) The majority of environment‐supporting innate immune structural cell types are anatomically positioned to be directly exposed to PAMPs and DAMPs. (3) Endothelial cells, as prototypic environment‐supporting innate immune structural cells, redefine the architecture of innate immunity. (4) Environment‐supporting innate immune structural cells have been historically underrecognized for their immune functions. (5) Neuron‐associated structural cell types exhibiting innate immune features suggest a potential role for neural cells in tissue‐specific inflammatory regulation. This work establishes a new concept that environment‐supporting innate immune structural cells are indispensable components of innate immunity that bridge tissue physiology and immune defense. By redefining immunity as a cooperative network of migratory immune cells and resident structural sentinels, with endothelial cells and vascular smooth muscle cells serving as prototypic examples, this paradigm provides new mechanistic insight into tissue‐specific inflammation, immune responses and immune privilege, and chronic inflammatory disease pathogenesis. Importantly, it opens new therapeutic avenues aimed at selectively targeting structural cell–intrinsic immune programs in cardiovascular disease, infection, inflammation, autoimmunity, transplantation, and cancer.