Effect of soluble cleavage products of important receptors/ligands on efferocytosis: Their role in inflammatory, autoimmune and cardiovascular disease

Efferocytosis, the clearance of apoptotic cells (ACs), is a physiologic, multifaceted and dynamic process and a fundamental mechanism for the preservation of tissue homeostasis by avoiding unwanted inflammation and autoimmune responses through special phagocytic receptors. Defective efferocytosis is associated with several disease states, including cardiovascular disease and impaired immune surveillance, as occurs in cancer and autoimmune disease. A major cause of defective efferocytosis is non-functionality of surface receptors on either the phagocytic cells or the ACs, such as TAM family tyrosine kinase, which turns to a soluble form by cleavage/shedding or alternative splicing. Recently, soluble forms have featured prominently as potential biomarkers, indicative of prognosis and enabling targeted therapy using several commonly employed drugs and inhibitors, such as bleomycin, dexamethasone, statins and some matrix metalloproteinase inhibitors such as TAPI-1 and BB3103. Importantly, to design drug carriers with enhanced circulatory durability, the adaptation of soluble forms of physiological receptors/ligands has been purported. Research has shown that soluble forms are more effective than antibody forms in enabling targeted treatment of certain conditions, such as autoimmune diseases. In this review, we sought to summarize the current knowledge of these soluble products, how they are generated, their interactions, roles, and their potential use as biomarkers in prognosis and treatment related to inflammatory, cardiovascular, and autoimmune diseases.