Granzyme B as a therapeutic target: an update in 2022

Expert Opin Ther Targets. 2022 Nov;26(11):979-993. doi: 10.1080/14728222.2022.2161890. Epub 2022 Dec 27.

Abstract

Introduction: Granzyme B is a serine protease extensively studied for its implication in cytotoxic lymphocyte-mediated apoptosis. In recent years, the paradigm that the role of granzyme B is restricted to immune cell-mediated killing has been challenged as extracellular roles for the protease have emerged. While mostly absent from healthy tissues, granzyme B levels are elevated in several autoimmune and/or chronic inflammatory conditions. In the skin, its accumulation significantly impairs proper wound healing.

Areas covered: After an overview of the current knowledge on granzyme B, a description of newly identified functions will be presented, focussing on granzyme B ability to promote cell-cell and dermal-epidermal junction disruption, extracellular matrix degradation, vascular permeabilization, and epithelial barrier dysfunction. Progress in granzyme B inhibition, as well as the use of granzyme B inhibitors for the treatment of tissue damage, will be discussed.

Expert opinion: The absence of endogenous extracellular inhibitors renders extracellular granzyme B accumulation deleterious for the proper healing of chronic wounds due to sustained proteolytic activity. Consequently, specific granzyme B inhibitors have been developed as new therapeutic approaches. Beyond applications in wound healing, other autoimmune and/or chronic inflammatory conditions related to exacerbated granzyme B activity may also benefit from the development of these inhibitors.

Keywords: Granzyme B; inflammation; skin integrity; small molecule inhibitor; tissue remodeling; wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / physiology
  • Granzymes
  • Humans
  • Wound Healing*

Substances

  • Granzymes

Grant support