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Evidence for a Hyperexcitability State of Staggerer Mutant Mice Macrophages

Abstract: We recently reported an abnormal production of interleukin‐1 (IL‐1) in peripheral macrophages of several neurological mutant mice that exhibit patterns of neuronal degeneration, especially in the cerebellum. After in vitro activation by lipopolysaccharide acid (LPS), these macrophages hyperexpress IL‐1β mRNA and hyperproduce IL‐1 protein in comparison with +/+ controls. In the present study, focused on the staggerer mutant mice, we investigate if this genetic dysregulation is specific for IL‐1β or if it reflects a generalized hyperexcitability of these macrophages. The hyperexpression of IL‐1β mRNA in sg/sg macrophages is present whatever the duration of LPS stimulation, even for periods as short as 15 min, although it reaches a maximum after 4 h of stimulation. The hyperinducibility of sg/sg macrophages is observed even when very low doses of LPS are used (0.01 μg/ml) and reaches its maximum for 5 μg/ml LPS. Synthetic molecules (muramyl dipeptides), such as N‐acetylmuramyl‐L‐alanyl‐D‐isoglutamine or murabutide, known as macrophage activators, are also efficient in revealing the cytokine hyperexpression in sg/sg macrophages. In addition, hyperexpression of two other cytokines, i.e., tumor necrosis factor‐α and IL‐1α mRNAs, is also detected in LPS‐stimulated macrophages of mutant mice. Finally, the effect of an inhibitor of protein synthesis, cycloheximide, is similar in +/+ and sg/sg macrophages. As a whole, these data lead us to conclude that the sg/sg macrophages are in a state of general hyperexcitability when compared with +/+ ones.