Alpha-2-Macroglobulin in Inflammation, Immunity and Infections

Abstract

Alpha-2-macroglobulin is an extracellular macromolecule mainly known for its role as a broad-spectrum protease inhibitor. By presenting itself as an optimal substrate for endopeptidases of all catalytic types, alpha-2-macroglobulin lures active proteases into its molecular cage and subsequently ‘flags’ their complex for elimination. In addition to its role as a regulator of extracellular proteolysis, alpha-2-macroglobulin also has other functions such as switching proteolysis towards small substrates, facilitating cell migration and the binding of cytokines, growth factors and damaged extracellular proteins. These functions appear particularly important in the context of immune-cell function. In this review manuscript, we provide an overview of all functions of alpha-2-macroglobulin and place these in the context of inflammation, immunity and infections.

Identification and Validation of Autophagy-Related Genes in Vitiligo

“…TGM2 is an enzyme that catalyzes the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. There were studies showing that A2M played an important role in the function of many immune cells [ 32 ], and TGM2 was involved in several autoimmune diseases such as celiac disease [ 33 ], inflammatory bowel disease, osteoarthritis, and idiopathic inflammatory myopathies [ 34 ]. However, little is known about the function of A2M and TGM2 in vitiligo, which needs to be explored in the future.…”

Faster skin wound healing predicts survival after myocardial infarction

“…The absence of skin wounding in the second cohort of animals in combination with comparable results in both cohorts indicate that skin wounding had no preconditioning effect on the MI response. A2M is a broad spectrum protease inhibitor and an acute phase protein involved in nonspecific inflammatory response to tissue injury ( 52 ). Interleukins and tumor necrosis factor-α released during tissue injury stimulate hepatocytes to increase production of A2M ( 53 ).…”

Cryo-EM structures reveal a dynamic transformation process of human alpha-2-macroglobulin working as a protease inhibitor

“…This is the way A2M gets rid of the excessive proteases in blood. Alternatively, the receptor LRP1 has the potential to activate various signaling pathway in target cells, including cell proliferation, cytoskeleton reconstruction, cell adhesion and apoptosis (10), which enable A2M to play an important role to modulate multiple further physiological processes, involving neutrophils migration and adhesion, macrophages phagocytosis, etc. Different from "Venus trap", nA2M in prokaryotes such as ECAM and SCAM seems involve a different way to convert into iA2M when trapping substrate proteases, that's called "Snap-trap".…”

“…The interaction of iA2M with its receptor leads to the clearance of A2M-substrate complex from circulation through cell endocytosis (1, 2). Alternatively, iA2M can be a diverse modulator as LRP1 potentially activates various signaling pathway, involving cell proliferation and adhesion, cytoskeleton reconstruction, and apoptosis in target cells (10), In addition, a number of cytokines and growth factors interact with nA2M but increasingly or preferentially with iA2M to prevent from proteolysis or to modulate their activities.…”

“…Both the native and induced forms of A2M bind a number of cytokines, growth factors to different degrees and with different efficiency to regulate their activities. Interestingly, induced A2M was found to perform more functions like activating the signaling cascades in target cell that facilitates neutrophil migration, improves cell division of macrophages, promotes bacterial phagocytosis and antigen presentation by macrophages (1, [3][4][5][6][7][8][9][10]. Moreover, induced A2M was found to inhibit amyloid formation and hypochlorite-induced A2M dimer with potent chaperone activity helps to remove the damaged proteins through lipoprotein receptors (1, 10).…”