Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma.
The cytotoxic granzyme B (GrB)/perforin pathway has been traditionally viewed as a primary mechanism that is used by cytotoxic lymphocytes to eliminate allogeneic, virally infected and/or transformed cells. Although originally proposed to have intracellular and extracellular functions, upon the discovery that perforin, in combination with GrB, could induce apoptosis, other potential functions for this protease were, for the most part, disregarded. As there are 5 granzymes in humans and 11 granzymes in mice, many studies used perforin knockout mice as an initial screen to evaluate the role of granzymes in disease. However, in recent years, emerging clinical and biochemical evidence has shown that the latter approach may have overlooked a critical perforin-independent, pathogenic role for these proteases in disease. This review focuses on GrB, the most characterized of the granzyme family, in disease. Long known to be a pro-apoptotic protease expressed by cytotoxic lymphocytes and natural killer cells, it is now accepted that GrB can be expressed in other cell types of immune and nonimmune origin. To the latter, an emerging immune-independent role for GrB has been forwarded due to recent discoveries that GrB may be expressed in nonimmune cells such as smooth muscle cells, keratinocytes, and chondrocytes in certain disease states. Given that GrB retains its activity in the blood, can cleave extracellular matrix, and its levels are often elevated in chronic inflammatory diseases, this protease may be an important contributor to certain pathologies. The implications of sustained elevations of intracellular and extracellular GrB in chronic vascular, dermatological, and neurological diseases, among others, are developing. This review examines, for the first time, the multiple roles of GrB in disease pathogenesis.
Boivin
Wendy Anne
WA
UBC James Hogg Research Laboratory, Providence Heart and Lung Institute at St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada.
Cooper
Dawn Michelle
DM
Hiebert
Paul Ryan
PR
Granville
David James
DJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000201:enzymology*; D053804:Granzymes / Q000502:physiology*; D006801:Humans; D007109:Immunity / Q000502:physiology*; D042541:Intracellular Space / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D054353:Perforin / Q000502:physiology
D054353:Perforin; D053804:Granzymes