An independent endocytic pathway stimulates different monocyte subsets by the a2 N-terminus domain of vacuolar-ATPase.

摘要

The vacuolar ATPase (V-ATPase) plays an important role in tumor progression andmetastases. A novel peptide from the a2 isoform of V-ATPase called a2NTD has beenshown to exert an immunoregulatory role in the tumor microenvironment bycontrolling the maturation of monocytes toward a tumor-associated macrophagephenotype. Our data indicate that a2NTD binds to the surface of monocytes. a2NTD was preferentially endocytosed by pro-inflammatory monocytes bearing aCD14(++)CD16(+) phenotype, which is associated with the monocyte-to-macrophagematuration process. Both a2NTD binding and internalization led to production ofthe pro-inflammatory cytokines interleukin (IL)-1α and IL-1β by CD14(++)CD16(-)(classical) and CD14(++)CD16(+) (intermediate) monocytes. a2NTD was internalized via a macropinocytosis mechanism utilizing scavenger receptors. However, theinhibition of a2NTD endocytosis did not reduce cytokine production by monocytes. This points to the existence of two receptors that respond to a2NTD: scavengersreceptors that mediate cellular uptake and an hitherto unidentified receptorstimulating the production of inflammatory cytokines. Both of these monocytereceptors may be important in generating the localized inflammation that is oftenrequired to promote tumor growth and hence may constitute novel targets for thedevelopment of anticancer drugs.