VAMP8 is essential in anaphylatoxin-induced degranulation, TNF-alpha secretion, peritonitis, and systemic inflammation.
VAMP8, a member of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) family of fusion proteins, initially characterized in endosomal and endosomal-lysosomal fusion, may also function in regulated exocytosis. VAMP8 physiological function in inflammation has not been elucidated. In this paper, we show that deficiency of VAMP8 protects mice from anaphylatoxin (C5a)-induced neutropenia, peritonitis, and systemic inflammation. We show that, in vivo, VAMP8 deletion inhibits neutropenia and phagocyte recruitment. We also show that in macrophages, VAMP8 localizes on secretory granules and degranulation is inhibited in VAMP8-deficient macrophages. Moreover, VAMP8(-/-) mice show reduced systemic inflammation with inhibition of serum TNF-alpha levels, whereas IL-1beta, IL-6, and MIP1alpha release are not affected. In wild-type macrophages, TNF-alpha colocalizes with VAMP8-positive vesicles, and in VAMP8-deficient macrophages, the TNF-alpha release is inhibited. Furthermore, VAMP8 regulates the release of TNF-alpha and beta-hexosaminidase triggered by fMLP, and VAMP8(-/-) mice are protected from fMLP-induced peritonitis. These data demonstrate that the VAMP8 vesicle-associated-SNARE is required for the proper trafficking of secretory lysosomal granules for exocytosis in macrophages and for the release of the potent proinflammatory cytokine, TNF-alpha.
Pushparaj
Peter N
PN
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
Tay
Hwee Kee
HK
Wang
Cheng-Chun
CC
Hong
Wanjin
W
Melendez
Alirio J
AJ
D000706:Anaphylatoxins / Q000494:pharmacology*; D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects*; D016207:Cytokines / Q000097:blood; D005089:Exocytosis; D007155:Immunologic Factors; D007249:Inflammation; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000633:toxicity; D009503:Neutropenia; D010538:Peritonitis / Q000139:chemically induced; D010586:Phagocytes; D050683:R-SNARE Proteins / Q000172:deficiency / Q000502:physiology*; D022142:Secretory Vesicles; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000706:Anaphylatoxins; D016207:Cytokines; D007155:Immunologic Factors; D050683:R-SNARE Proteins; D014409:Tumor Necrosis Factor-alpha; C491831:Vamp8 protein, mouse; D009240:N-Formylmethionine Leucyl-Phenylalanine