Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Abstract

Interleukin (IL)-1␤ and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. There is increasing evidence that cathepsin B (CatB), a typical lysosomal cysteine protease, is involved in the pro-caspase-1 activation and the subsequent maturation of IL-1␤ and IL-18. In this context, CatB is considered to be an important molecular target to control chronic pain. However, no information is currently available about the role of CatB in chronic pain hypersensitivity. We herein show that CatB deficiency or the intrathecal administration of CA-074Me, a specific CatB inhibitor, significantly inhibited the induction of complete Freund's adjuvant-induced tactile allodynia in mice without affecting peripheral inflammation. In contrast, CatB deficiency did not affect the nerve injury-induced tactile allodynia. Furthermore, CatB deficiency or CA-074Me treatment significantly inhibited the maturation and secretion of IL-1␤ and IL-18 by cultured microglia following treatment with the neuroactive glycoprotein chromogranin A (CGA), but not with ATP. Moreover, the IL-1␤ expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1␤ and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.

Cathepsin B Contributes to Autophagy-related 7 (Atg7)-induced Nod-like Receptor 3 (NLRP3)-dependent Proinflammatory Response and Aggravates Lipotoxicity in Rat Insulinoma Cell Line

“…CTSB, a lysosomal cysteine protease, has been suggested to be involved in autophagyinduced inflammasome formation (31,32). We report here that the increased level of CTSB induced by Atg7 transfection acted as a stimulus, which was demonstrated to trigger NLRP3 activation and promote caspase-1-dependent proinflammatory cytokine secretion and may enhance pathogenesis in type 2 diabetes (33).…”

Amblyomma americanum tick saliva serine protease inhibitor 6 is a cross‐class inhibitor of serine proteases and papain‐like cysteine proteases that delays plasma clotting and inhibits platelet aggregation

“…Thus, the observation in the present study that r Aam S6 inhibited proteolytic activity of chymase and elastase may suggest a role for Aam S6 in mediating the tick's anti‐inflammation function at the tick feeding site. Similarly, papain‐like cysteine proteases are associated with cellular surfaces of cellular mediators of inflammation, macrophages and neutrophils (Jevnikar et al ., ; Sun et al ., ; Vendramini‐Costa & Carvalho, ). Thus, there is also a possibility that Aam S6 might interfere with the inflammation response by blocking cysteine protease function.…”

Glycogen synthase kinase 3 beta regulates glial glutamate transporter protein expression in the spinal dorsal horn in rats with neuropathic pain

“…Proteases like cathepsin B, caspase-1, and MMP2 are implicated in different pathological pain conditions. Suppression of cathepsin B (Sun et al, 2012), caspase-1 activities (Samad et al, 2001) in the spinal dorsal horn attenuates inflammatory pain induced by CFA through reducing production of IL-1β. In rats with neuropathic pain, production of IL-1β and abnormal nociceptive behaviors are reduced by inhibiting MMP2 activities (Kawasaki et al, 2008a).…”