"Calpains : a double edged sword in ischemia, inflammation, and fibrosis"
Calpains are calcium-activated neutral cysteine proteases, which are ubiquitously expressed. They play potentially a role in inflammation, as they are involved in NF-kB-dependent expression of pro-inflammatory cytokines, in inflammatory mediator processing, in inflammatory cell chemotaxis, and in cleavage of HSP 90, which is required to maintain binding and anti-inflammatory efficacy of glucocorticoid. Calpain activity is tightly controlled by calpastatin, a specific endogenous inhibitor. Thus, to identify precisely calpain roles in inflammation, we created mice transgenic for calpastatin. Using this original tool, we ascertained the functions of calpains in models of glomerulonephritis, hypertension, and transplantation.
Interestingly, calpains are externalized during inflammatory process. Using in vitro and in vivo approaches, we found that externalized calpains play a paradoxical role in limiting inflammatory reaction and promoting tissue repair. It will be of interest to focus on novel anti-inflammatory drugs that increase calpain secretion, as this strategy would decrease the availability of intracellular calpains (pro-inflammatory) and increase that of extracellular calpains (anti-inflammatory). Meanwhile ongoing studies aim at identifying molecular mechanisms of calpain secretion.