Bactericidal Activity of Alveolar Macrophages is Suppressed by V-ATPase Inhibition

Abstract

Bafilomycin A(1), a selective inhibitor of V-type H(+)-translocating ATPase (V-ATPase), may be a useful adjunct in cancer chemotherapy (Altan et al. [1998] J Exp Med 187:1583-1598). Therapeutic uses of the enzyme inhibitor need to consider the agent's potential effects on normal (nontumor) cells. This study determined the effects of bafilomycin A(1) on resident alveolar macrophages (mphi). Treatment of alveolar mphi with bafilomycin A(1) (10 microM, 1 h) caused a significant decrement in cytosolic pH. This was accompanied by marked alteration of mphi bactericidal capabilities. The enzyme inhibitor caused a marginal reduction in the phagocytosis of opsonized Staphylococcus aureus and significantly suppressed intracellular killing of the phagocytosed bacteria. In keeping with the effects on intracellular killing, bafilomycin A(1) significantly reduced the production of reactive oxygen species (ROS). On the other hand, cell spreading was enhanced significantly by bafilomycin A(1). Comparable changes in ROS generation and mphi spreading were produced by altering cytosolic pH through changes in extracellular pH (pH(o)) in the absence of bafilomycin A(1). These findings suggest that the agent's effects on ROS production and mphi spreading were related to the accompanying changes in cytosolic pH. The enzyme inhibitor also altered mphi morphology, leading to the shortening of microvilli and focal loss of surface ruffles. These morphologic effects differed from those produced by altering cytosolic pH by changes in pH(o). The results demonstrate that V-ATPase activity is an important determinant of mphi functioning and structure. Therapeutic use of V-ATPase inhibitors might be expected to compromise the bactericidal activity of alveolar mphi.

Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

“…[8][9][10][11][12][13][14][15] The study was extended to six SNPs (rs36027301, rs4147779, rs2471829, rs4147778, rs4147780 and rs2075609), which are not found in patients affected with osteopetrosis. 4 The corresponding alleles were therefore expected to be present in the population at a reasonable frequency.…”

“…6,7 Bafilomycin A 1 (an inhibitor of V-ATPase) reduces significantly the intracellular killing of phagocytosed M tuberculosis 8 and the production of reactive oxygen species. 8 Both these activities contribute significantly to the antimicrobial activity of the phagocytic cell. 8 Exclusion of V-ATPase from phagosomes also blocks the processing of Mycobacterium antigens by the macrophages.…”

“…8 Both these activities contribute significantly to the antimicrobial activity of the phagocytic cell. 8 Exclusion of V-ATPase from phagosomes also blocks the processing of Mycobacterium antigens by the macrophages. [7][8][9] Thus, M. tuberculosis curbs both the functions of macrophages, as phagocytic cells and as antigenpresenting cells.…”

“…8 Exclusion of V-ATPase from phagosomes also blocks the processing of Mycobacterium antigens by the macrophages. [7][8][9] Thus, M. tuberculosis curbs both the functions of macrophages, as phagocytic cells and as antigenpresenting cells. In addition, V-ATPase suppresses the expression of macrophage-derived pro-inflammatory cytokines, in particular of TNF-a, 10 which is essential for the control of M. tuberculosis infection: too little as well as too much production of this cytokine predisposes to pulmonary tuberculosis.…”

Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases

“…22 Activation of neutrophils via the protein kinase C pathway causes upregulation of V-ATPase activity, and it is suggested that this is necessary to maintain intracellular pH during the metabolic burst associated with neutrophil activation, degranulation and phagocytosis. 23 Studies in alveolar macrophages have demonstrated that inhibition of V-ATPase reduces TNF production 24 and bactericidal activity, 25 suggesting an important role for this enzyme in the inflammatory functioning of macrophages. The maturation of dendritic cells is associated with a substantial increase in V-ATPase activity, regulated mainly by recruitment of inactive subunits.…”