Interleukin‐1 Hyperproduction by In Vitro Activated Peripheral Macrophages from Cerebellar Mutant Mice

Abstract

Several mutations in mice produce complex patterns of neuronal degeneration of the cerebellum and of its afferent pathways. In the staggerer (sg/sg) mutant, atrophy of the lymphoid organs and immunological abnormalities have been described. To search for a possible link between the neurological and the immune disorders in this mutant, we studied the production by its peripheral macrophages of interleukin-1 (IL-1), which roles in both immune and nervous systems are well established. Suspensions of peritoneal and/or spleen macrophages from mutants and their appropriate controls were stimulated in vitro by lipopolysaccharide. Northern and dot blots, performed with murine IL-1 cDNA probes, revealed a clear-cut hyperexpression of IL-1 mRNA in staggerer macrophages. An IL-1 bioassay using the IL-1-responsive D10.G4 cell line also revealed a sixfold increase of IL-1 activity in the macrophage supernatants of staggerer mutant mice. The hyperproduction was found in 3-week to 1-year-old staggerer and also in heterozygous (+/sg) mice. A similar phenomenon existed in cerebellar mutants lurcher, Purkinje cell degeneration (pcd), and to a lesser extent reeler and wobbler, but was absent in the neurological mutants weaver, jimpy, and motor end plate disease (medH). These observations establish that in several point mutations in mice, central nervous degeneration is associated with dysregulation of IL-1 production by peripheral macrophages.

Identification of Reverbα as a Novel RORα Target Gene

“…However, ROR␣ is also able to bind to DR-2 elements as a homodimer in vitro (12). Similar to ROR␥, ROR␣ has been reported to regulate negatively the inflammatory response (13,14) by antagonizing, at least in part, the NF-B signaling pathway (14). Moreover, analysis of ROR␣-deficient mice suggests an important function of ROR␣ in the development of the central nervous system (15)(16)(17).…”

Morphology of Adrenal Gland and Lymph Organs is Impaired in Neurodeficient Lurcher Mutant Mice

“…A similar "IL-1 phenomenon" like in Lurchers and staggerers exists in Purkinje cell degeneration (pcd) mutants and to a lesser extent in reeler and wobbler mice, but was absent in the neurological mutants weaver, jimpy, and motor end plate disease (medH) (Kopmels et al 1990). The above mentioned studies lead us to the hypothesis that the neuronal degeneration affecting the cerebellum in different mutant mice do not lead to the same immunological defect at the peripheral level.…”

“…the staggerer mice, the Lurcher mutants display certain abnormalities in endocrine and immune functions. They exhibit an enhanced adrenocorticotropic hormone (ACTH) and corticosterone response to novel enviromental stress and endotoxin (Frederic et al 1997) and also an abnormal production of some proinflammatory cytokines that modulate immune as well as endocrine functions (Bakalian et al1992;Kopmels et al 1990).…”

A circadian based inflammatory response – implications for respiratory disease and treatment

“…This has been shown with deletion of Ror-α in mice which leads to abnormal immune responses such as hyper responsive macrophages producing higher levels of cytokines in bronchoalveolar lavage fluids after LPS challenge (Sidman et al 1962;Kopmels et al 1990;Trenkner and Hoffmann 1966;Stapleton et al 2005;Dzhagalov et al 2004). Macrophages from Rev.-erb-α −/− mice and from LysM-Bmal −/− mice (mice that lack Bmal1 in their macrophages, monocytes and neutrophils) show loss of circadian gating and constitutively elevated levels of IL-6 in response to the LPS challenge (Gibbs et al 2012).…”