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UBC Theses and Dissertations

The role of Malt1 in macrophages and osteoclasts Monajemi, Mahdis


Combined immunodeficiency caused by a homozygous mutation in the mucosa associated lymphoid tissue 1 (MALT1) gene is associated with severe inflammation along the gastrointestinal tract and osteoporosis, which were corrected by hematopoietic stem cell transplant (HSCT). The consequences of Malt1 deficiency have largely been attributed to its role in lymphocytes, but Malt1 is also expressed in myeloid cells. The effect of Malt1 deficiency in macrophages and osteoclasts and their contribution to inflammatory bowel disease (IBD) and osteoporosis respectively have not been investigated. My objectives were to determine the contribution of Malt1-/- macrophages to dextran sodium sulfate (DSS)-induced colitis in mice and to assess the effect of innate immune stimuli on Malt1-/- macrophage inflammatory responses. I also studied the level of Malt1 expression during intestinal inflammation in humans and mice. I next asked whether Malt1-deficient mice develop an osteoporosis-like phenotype and whether it is caused by the effect of Malt1 deficiency on osteoclast differentiation and/or activity. I found that Malt1 deficiency exacerbates DSS-induced colitis in mice, and that macrophages and IL-1 signaling contribute to pathology in Malt1-/- mice. Innate immune stimuli induced Malt1 protein levels in murine macrophages in vitro. However, intestinal inflammation did not have any effect on Malt1 expression in humans and mice in vivo. I also found that adult Malt1-deficient mice have lower bone volume, and Malt1 expression and activity is induced by receptor activator of nuclear factor κB ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro but their number was higher in Malt1-/- mice in vivo. Inhibition of Malt1 activity in macrophages after activation by inflammatory stimuli induced macrophage colony-stimulating factor (MCSF) production, required for osteoclastogenesis, and decreased OPG production, an endogenous inhibitor of osteoclastogenesis, which was also lower in Malt1-/- mice serum. Taken together, these data demonstrate that Malt1-/- mice are more susceptible to DSS-induced colitis through higher IL-1 production by Malt1-/- macrophages and these mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, which is caused by inflammation rather than a cell-intrinsic effect of Malt1 deficiency in osteoclasts.

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