MALT1 inhibitors prevent the development of DSS-induced experimental colitis in mice via inhibiting NF-κB and NLRP3 inflammasome activation

Abstract

Mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), a paracaspase and essential regulator for nuclear factor kB (NF-κB) activation, plays an important role in innate and adaptive immunity. Suppression of MALT1 protease activity with small molecule inhibitors showed promising efficacies in subtypes of B cell lymphoma and improvement in experimental autoimmune encephalomyelitis model. However, whether MALT1 inhibitors could ameliorate colitis remains unclear. In the present study, we examined the pharmacological effect of two specific MALT1 inhibitors MI-2 and mepazine on the dextran sulfate sodium (DSS)-induced experimental colitis in mice, followed by mechanistic analysis on NF-κB and NLRP3 inflammasome activation. Treatment with MI-2 and mepazine dose-dependently attenuated symptoms of colitis in mice, evidenced by reduction in the elevated disease activity index, the shortening of colon length as well as the histopathologic improvement. Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF, IL-1β, IL-6, IL-18, IL-17A and IFN-γ, were markedly suppressed by MALT1 inhibitors. The underlying mechanisms for the protective effect of MALT1 inhibitors in DSS-induced colitis may be attributed to its inhibition on NF-κB and NLRP3 inflammasome activation in macrophages. The in vitro study showed that MALT1 inhibitors decreased production of IL-1β/IL-18 in phorbol myristate acetate-differentiated THP-1 cells and bone marrow derived macrophage via suppressing the activation of NF-κB and NLRP3 inflammasome. Taken together, our results demonstrated that inhibition of the protease activity of MALT1 might be a viable strategy to treat inflammatory bowel disease and the NLRP3 inflammasome and NF-κB activation are critical components in MALT1 signaling cascades in this disease model.

Canonical and Non-Canonical Activation of NLRP3 Inflammasome at the Crossroad between Immune Tolerance and Intestinal Inflammation

“…In further support of the above data, a recent paper by Liu et al (65) showed that the inhibition of mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), a scaffold protein, which recruits the IκB kinase complex leading to release and activation of NF-κB, ameliorated clinical symptoms and histopathologic features of DSS-induced colitis through NF-κB and NLRP3 inhibition, thus interfering with both inflammasome activation steps (65, 66). In particular, treatment with two specific MALT1 inhibitors, MI-2 and mepazine, dose-dependently attenuated the symptoms of colitis in mice through a decrease in protein and mRNA levels of colonic TNF, IL-1β, IL-6, IL-18, IL-17A, and IFN-γ pro-inflammatory cytokines (66).…”

Malt1 blocks IL-1β production by macrophages in vitro and limits dextran sodium sulfate-induced intestinal inflammation in vivo

“…Malt1 expression and proteolytic activity are clearly important in mucosal homeostasis. Inhibition of Malt1 paracaspase activity with 2 distinct paracaspase inhibitors, MI‐2 and MPZ, protects mice during DSS‐induced colitis . This correlates with decreased NFκB and NLRP3 activation and decreased IL‐1β and IL‐18 production by PMA‐differentiated THP‐1 cells and bone marrow macrophages, and is consistent with paracaspase activity enhancing Malt1 scaffolding function and augmenting NFκB‐mediated transcription .…”

“…Inhibition of Malt1 paracaspase activity with 2 distinct paracaspase inhibitors, MI‐2 and MPZ, protects mice during DSS‐induced colitis . This correlates with decreased NFκB and NLRP3 activation and decreased IL‐1β and IL‐18 production by PMA‐differentiated THP‐1 cells and bone marrow macrophages, and is consistent with paracaspase activity enhancing Malt1 scaffolding function and augmenting NFκB‐mediated transcription . In contrast, mice deficient in Malt1 paracaspase activity ( Malt1 PD/− ) do significantly worse than their Malt1‐sufficient counterparts ( Malt1 +/− ) during DSS‐induced colitis .…”

“…Inhibition of Malt1 activity in macrophages has been reported to reduce IL‐1β production by macrophages . IL‐1β is produced by macrophages in the gut and was elevated in DSS‐induced colitis in Malt1 −/− mice; and IL‐1β has been identified as an important mediator of inflammation in DSS‐induced colitis .…”

Micro Integral Membrane Protein (MIMP), a Newly Discovered Anti-Inflammatory Protein of Lactobacillus Plantarum, Enhances the Gut Barrier and Modulates Microbiota and Inflammatory Cytokines

“…The colitis model was established by DSS induction according to a previous description [18]. Briefly, we divided eighteen 10-week-old male C57BL6 mice into 3 groups: healthy control group (n=6), DSS-treated group (n=6), and MIMP-treated group (n=6).…”