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.

Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency

“…We, and Gewies et al., have reported that both germline deficient mice and mice deficient in paracaspase activity are more susceptible to dextran sodium sulfate‐induced colitis . In our study, we further demonstrated that increased inflammation and pathology in Malt1 −/− mice is driven by Mϕ‐derived IL‐1β production . This work suggests that innate immune (and myeloid) cells are poised to respond more robustly to activating stimuli in Malt1 deficient mice.…”

“…T cell defects have been demonstrated in both mice strains because T cells from these mice do not cause inflammation in the T cell transfer model of colitis; and both mouse genotypes, as well as inhibition of paracaspase activity, are protective in an experimental mouse model of autoimmune encephalitis, which is driven by the development of pathological Th17 cells . We, and Gewies et al., have reported that both germline deficient mice and mice deficient in paracaspase activity are more susceptible to dextran sodium sulfate‐induced colitis . In our study, we further demonstrated that increased inflammation and pathology in Malt1 −/− mice is driven by Mϕ‐derived IL‐1β production .…”

“…We next asked whether Malt1 was expressed and active in bone marrow‐derived osteoclasts from wild‐type mice. Osteoclasts were derived from bone marrow precursors and Malt1 protein levels were compared to that seen in Mϕs, in which we have demonstrated that Malt1 is expressed and active . Mϕs and osteoclasts (10 6 cells/well) were analyzed by western blotting for Malt1, Bcl‐10 (a Malt1 substrate), and Gapdh, as a loading control.…”

“…A). Mϕs are a source of both MCSF and OPG and we have previously reported that Malt1 deficient Mϕs are hyper‐responsive to innate immune stimuli . Thus, we stimulated wild‐type Mϕs with LPS, zymosan (Zym), or curdlan (Cur) ± the Malt1 inhibitor, MPZ, and measured MCSF and OPG production.…”

“…In summary, the patient with MALT1 deficiency had growth inhibition and severe osteoporosis, both of which improved significantly post‐HSCT . We have reported that Malt1 deficiency leads to hyper‐activation of Mϕs in Malt1 −/− mice . Osteoclasts, like Mϕs, are derived from myeloid precursors and could contribute to the HSCT‐corrected bone phenotype observed in the MALT1 deficient patient.…”