Reprogramming Innate Immune Signaling in Cardiometabolic Disease

Innate immunity is the first line of host defense and is primarily initiated via the activation of germ line-encoded pattern-recognition receptor (PRR)–mediated innate immune signaling.1 Although many innate immune mechanisms have been identified, integrated knowledge of the function and regulation of innate immune signaling remains in its infancy. Evolutionary evidence reveals that Toll-like receptors (TLRs), retinoic acid–inducible gene I–like receptors (RLRs), and their adaptor genes are conserved in jawless vertebrates; however, IRF3 , IRF7 , type I IFN , and inflammatory cytokine genes, such as TNF-α , IL - 12p40 , and IL-6 , do not exist in jawless vertebrates.2 These observations imply that the TLR- and RLR-mediated conventional innate immune signaling pathways are incomplete in jawless vertebrates, and the molecular basis of the innate immune system in jawless vertebrates may be distinct from that of jawed vertebrates. Therefore, these evidences raise the following questions: What is the function of preexisting innate immune signaling? If it can perform host defense functions, what is the mechanism? If not, the preexisting signaling may perform nonimmune functions because of the lack of certain transcription factors and cytokine genes. Innate immune response pathways and cardiometabolic pathways are evolutionarily conserved throughout species and are fundamental for survival.3 Therefore, cardiometabolic regulation and immune responses are intimately integrated and functionally dependent.4 In addition to the activation of immune cells, innate immune signaling also affects the function of nonimmune cells in metabolic organs and the cardiovascular system, thus influencing the development of cardiometabolic disease (CMD), a common and complex disorder that involves a cluster of symptoms, including obesity, insulin resistance, diabetes mellitus, hypertension, dyslipidemia, hepatic steatosis, atherosclerosis, ischemic heart diseases, and cardiac hypertrophy and fibrosis.5 Importantly, these signals may act not only by immune-dependent manners but also by immune-independent mechanisms, with the latter …