The Genetic Background of Mice Influences the Effects of Cigarette Smoke on Onset and Severity of Experimental Autoimmune Encephalomyelitis

Abstract

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults leading to severe disability. Besides genetic traits, environmental factors contribute to MS pathogenesis. Cigarette smoking increases the risk of MS in an HLA-dependent fashion, but the underlying mechanisms remain unknown. Here, we explored the effect of cigarette smoke exposure on spontaneous and induced models of experimental autoimmune encephalomyelitis (EAE) by evaluating clinical disease and, when relevant, blood leukocytes and histopathology. In the relapsing-remitting (RR) transgenic model in SJL/J mice, we observed very low incidence in both smoke-exposed and control groups. In the optico-spinal encephalomyelitis (OSE) double transgenic model in C57BL/6 mice, the early onset of EAE prevented a meaningful evaluation of the effects of cigarette smoke. In EAE models induced by immunization, daily exposure to cigarette smoke caused a delayed onset of EAE followed by a protracted disease course in SJL/J mice. In contrast, cigarette smoke exposure ameliorated the EAE clinical score in C57BL/6J mice. Our exploratory studies therefore show that genetic background influences the effects of cigarette smoke on autoimmune neuroinflammation. Importantly, our findings expose the challenge of identifying an animal model for studying the influence of cigarette smoke in MS.

Effects of cigarette smoke exposure on a mouse model of multiple sclerosis

“…The body weight of most affected mice began to stabilize and increase after 23 days post-immunization, paralleling a slight decrease in clinical scores by 0.5 or 1 before the scores stabilized. These fluctuations in EAE progression are in agreement with previous reports [104] , [20] , [23] , [78] . In addition, mice exposed to low and medium concentrations of CS showed a general tendency towards more severe disease symptoms.…”

“…Initial assessment of the brain sections by hematoxylin and eosin staining revealed a limited number of noticeable lesions in some sections, and the differences between the treatment groups were not observable (data not shown); thus, no further analyzes were conducted for the brain. This observation is in agreement with those from previous studies showing limited central nervous system (CNS) infiltrates and no evidence of brain lesions in MS mouse models [20] , [54] . We have also observed that EAE induction, which induces more severe clinical symptoms, does not necessarily induce brain pathology and primarily affects spinal cord pathology, particularly in the lumbar region (unpublished data).…”

“…On the other hand, initial assessment of the brain sections by hematoxylin and eosin staining revealed a limited number of noticeable lesions in some sections, and the differences between the treatment groups were not observable (data not shown); thus, no further analyzes were conducted for the brain. Even though limited CNS infiltrates and brain lesions similar to ours were reported in MS mouse models [20] , [54] , some recent advance analyses enabled further insights at the lesion formation in the brain [109] , [27] , [74] .

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“…Furthermore, different constituents of CS have been reported to have pro- and anti-inflammatory effects in nonclinical studies that might differentially affect EAE disease outcomes depending on their concentrations [51] . For example, a previous study linked the delayed onset of EAE after CS exposure to the modifications of microglia via nicotinic acetylcholine receptors (nAChR) in SJL and C57BL/6 mice [20] , indicating the importance of nicotine alkaloids in regulating the EAE outcome. In addition to nicotine alkaloids, several bioactive agents present in CS, such as nicotine, carbon monoxide, acrolein, and reactive oxygen species, have immunomodulatory effects [51] .…”

“…Although the epidemiological data on the effect of cigarette smoking on MS are important, there have been limited systematic investigations under controlled laboratory conditions to study a direct cause-and-effect relationship between CS exposure and MS development and prognosis. Among several animal models for MS, EAE is the most commonly used experimental model for studying pathogenesis and discovering pharmacological therapies for MS, and it has been used to test a number of compounds [117] , [16] , [20] , [23] , [78] , [96] . In addition, all the current US Food and Drug Administration (FDA)-approved immunomodulatory drugs are found effective to some degree in treating EAE, therefore it is a strong indicator that EAE is the preferred model to study autoimmune response aspects of MS and develop effective treatments for the human disease.…”