MALT1 inhibitors prevent the development of DSS-induced experimental colitis in mice via inhibiting NF-κB and NLRP3 inflammasome activation.
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.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Wen
W
Liu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Wenjie
W
Guo
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Nan
N
Hang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Yuanyuan
Y
Yang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Xuefeng
X
Wu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Yan
Y
Shen
Eternity Bioscience Inc, Cranbury, NJ 08512, USA.
Jingsong
J
Cao
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Yang
Y
Sun
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Qiang
Q
Xu
D000083:Acetanilides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
D000083:Acetanilides; D016207:Cytokines; D004791:Enzyme Inhibitors; D058847:Inflammasomes; C000612169:MI-2 acetamide; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010640:Phenothiazines; D014230:Triazoles; C100190:mepazine; D016264:Dextran Sulfate; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
IL-1β; MALT1; NF-κB; NLRP3 inflammasome; colitis