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

Abstract

This study tested the hypothesis that Malt1 deficiency in macrophages contributes to dextran sodium sulfate (DSS)-induced intestinal inflammation in Malt1-deficient mice. In people, combined immunodeficiency caused by a homozygous mutation in the MALT1 gene is associated with increased susceptibility to bacterial infections and chronic inflammation, including severe inflammation along the gastrointestinal tract. The consequences of Malt1 deficiency have largely been attributed to its role in lymphocytes, but Malt1 is also expressed in macrophages, where it is activated downstream of TLR4 and dectin-1. The effect of Malt1 deficiency in murine macrophages and its contribution to DSS-induced colitis have not been investigated. Our objectives were to compare the susceptibility of Malt1^+/+ and Malt1^-/- mice to DSS-induced colitis, to determine the contribution of macrophages to DSS-induced colitis in Malt1^-/- mice, and to assess the effect of innate immune stimuli on Malt1^-/- macrophage inflammatory responses. We found that Malt1 deficiency exacerbates DSS-induced colitis in mice, accompanied by higher levels of IL-1β, and that macrophages and IL-1 signaling contribute to pathology in Malt1^-/- mice. Malt1^-/- macrophages produce more IL-1β in response to either TLR4 or dectin-1 ligation, whereas inhibition of Malt1 proteolytic (paracaspase) activity blocked IL-1β production. TLR4 or dectin-1 stimulation induced Malt1 protein levels but decreased its paracaspase activity. Taken together, these data support the hypothesis that Malt1^-/- macrophages contribute to increased susceptibility of Malt1^-/- mice to DSS-induced colitis, which is dependent on IL-1 signaling. Increased IL-1β production by MALT1-deficient macrophages may also contribute to chronic inflammation in people deficient in MALT1.

Keywords: LPS; TLR4; curdlan; dectin-1; dextran sodium sulfate (DSS)-induced colitis; intestinal inflammation; zymosan.