Small heat shock protein CRYAB inhibits intestinal mucosal inflammatory responses and protects barrier integrity through suppressing IKKβ activity

Abstract

Alpha B-crystallin (CRYAB) is an important member of the small heat shock protein family, and plays a protective and therapeutic role in neurological inflammation. CRYAB expression was assessed in cultured HT29 and Caco-2 cells and inflamed mucosa of patients with inflammatory bowel disease (IBD) and colitis models in mice. Lentivirus-overexpressing and CRSIPR/Cas9 systems were used in different cells to upregulate and silence CRYAB expression, respectively. Cell permeable recombined fusion protein TAT-CRYAB was injected intraperitoneally into dextran sulfate sodium (DSS)-or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice to assess its anti-inflammatory effects. CRYAB was found to be significantly decreased in the inflamed mucosa from IBD patients and DSS-induced colitis in mice, and negatively correlated with the levels of TNF-α and IL-6, respectively. Enforced expression of CRYAB suppressed expression of proinflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, and IL-8) via inhibiting the IKK complex formation, whereas lack of CRYAB expression markedly enhanced proinflammatory responses. Consistently, administration of TAT-CRYAB fusion protein significantly alleviated DSS-or TNBS-induced colitis in mice and protected intestinal barrier integrity. CRYAB regulates inflammatory response in intestinal mucosa by inhibiting IKKβ-mediated signaling and may serve as a novel therapeutic approach in the treatment of IBD.

Inhibition of miR-450b-5p ameliorates hepatic ischemia/reperfusion injury via targeting CRYAB

“…It is worth noting that activation of canonical NF-κB pathway mediated by IKKβ showed relevance to CRYAB blockade, while NIK/IKKα remained invariant. What we testified was consistent with previous studies, in which CRYAB was proved to be a potent negative regulator of noncanonical NF-κB signal 14 .…”

“…As an important member of small heat-shock protein, CRYAB displays a proper role with identification of the anti-inflammatory effect 12,13 . Recent studies indicated that CRYAB could serve as a potential target in response to stimulation of inflammatory cytokines, through suppression of IKK in intestinal mucosal inflammation 14 . Given the pivotal role of IKK in the initiation of NF-κB signaling, CRYAB is likely to control the occurrence and progress of inflammation in hepatic IRI to some extent, the specific molecular mechanism of which needs an indepth exploration 8,15 .…”

Phosphorylation of the Chaperone-Like HspB5 Rescues Trafficking and Function of F508del-CFTR

“…Screening of molecules able to decrease CF chronic inflammation is an active area of research [37]. Recently, Xu et al [38] reported that HspB5 mRNA expression was decreased in inflamed mucosa of inflammatory bowel disease patients compared to noninflamed specimens. Interestingly, TAT-HspB5 recombinant protein administration alleviated intestinal mucosal inflammation in mice.…”

Molecular Chaperones: Molecular Assembly Line Brings Metabolism and Immunity in Shape

“…However, the administration of recombinant HSPB5 protein ameliorates EAE, suggesting an immunosuppressive and therapeutic role for HSPB5 during autoimmune demyelination [ 158 ]. Similarly, HSPB5 was found to regulate intestinal inflammation that inhibits IKKβ-mediated signaling to alleviate colitis symptoms and protect intestinal barrier integrity in animals [ 159 ]. The immune balance handled by sHSPs is dependent on their local concentrations.…”