Granzyme B and perforin: constitutive expression in human polymorphonuclear neutrophils

Abstract

Polymorphonuclear neutrophils (PMNs) produce an abundance of bactericidal and cytotoxic molecules consistent with their role as first-line defense against bacterial infection. PMNs, however, also cause efficient cellular cytotoxicity when targeted through Fc receptors to appropriate antibody-coated target cells. Although this so-called antibody-dependent cellular cytotoxicity (ADCC) was described many years ago, the mechanism of killing is still elusive. We now have found that PMNs contain perforin and granzyme B, the 2 molecules known as the cytotoxic entity of natural killer cells and of cytotoxic T lymphocytes as well. Lysates of PMNs were lytic for chicken erythrocytes in a time-, temperature-, and Ca 2؉ -dependent manner. Moreover, apoptosis of Jurkat cells was induced, consistent with the observation that the PMN lysates contain enzymatically active granzyme B. Taken together, our data provide evidence for the presence of perforin and granzyme B within the cytotoxic arsenal of PMNs.

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

“…It is unclear whether, during killer cell degranulation, the immune synapse forms a perfectly tight gasket that completely prevents granzymes from leaking out into the extracellular space. Moreover, increasing evidence suggests that granzymes may be expressed without perforin and secreted by other types of white blood cells during inflammation, including mast cells, neutrophils, activated macrophages, as well as potentially some nonhematopoietic cells, such as UV-damaged keratinocytes (7,10,11,(176)(177)(178). GzmB is even expressed by developing germ cells in the testes and by syncytial trophoblasts in the placenta (14).…”

“…In fact, GzmB has been found in bronchoalveolar lavage fluid after allergen exposure. Several studies have also provided evidence for the expression of GzmB and perforin in human neutrophils, but this is controversial (10)(11)(12)(13).…”

Control of granzymes by serpins

“…[21][22][23][24] This distribution at first seemed to be wider than that of gzmB, which was thought to be highly restricted to CLs. 25 However, it is now apparent that gzmB is expressed by a great diversity of cell types, including cells of both the myeloid [26][27][28][29] and lymphoid lineages, [30][31][32][33] as well as cells outside the immune system. 22,34,35 Thus, the distribution of SERPINB9 and gzmB predominantly overlaps.…”

“…Recently, it has been reported that gzmB is present in other leukocyte populations, namely, CD4 þ T cells, 33 B cells, 31 neutrophils, 29 basophils, 28 mast cells, 27 macrophages, 26 dendritic cells 32,52 and CD34 þ stem cells. 29,53 Although the function of gzmB produced by these cells is unknown, it seems to be granule associated.…”

“…29,53 Although the function of gzmB produced by these cells is unknown, it seems to be granule associated. 28 Not surprisingly, SERPINB9 is also present in most if not all of these cells, 24,54 suggesting that it provides protection against gzmB in these settings as well.…”