SMN deficiency alters the CNS and the peripheral immune system in a mouse model of spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss or mutation of the SMN1 gene. SMA rises from the insufficient levels of the ubiquitously expressed survival motor neuron (SMN) protein and is characterized by progressive α-lower motor neuron (LMN) degeneration and muscle atrophy. SMN is vital to all tissues, and the specific vulnerability of the LMN is still puzzling. However, currently there is a growing list of tissues affected in SMA. Recently, we have analyzed the development and the immune components of SMA spleen and found a selective reduction of the red pulp (RD) and RP macrophages in SMA mice, while white pulp and lymphocyte populations were largely preserved. Furthermore, previous studies suggested a role of glia cells in LMN pathology. These findings prompt us to investigate the role of the immune system in SMA pathogenesis. Looking into the cytokines production in the widely used “SMNΔ7” mouse model of SMA, we found that at steady state there is a higher production of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in SMA central nervous system (CNS) that starts at an early symptomatic age and escalates at the late symptomatic time. However, the anti-inflammatory cytokine TGF-β had lower expression. Interestingly, after in vivo LPS stimulation, SMA astrocytes and splenocytes exhibit less potency in increasing the pro-inflammatory cytokines except for IL-1β that had significantly higher levels in SMA at all points. These findings suggest that there is a role of SMN in the homeostasis and function of resident macrophages in the CNS and the spleen, and denote a yet undiscovered immune component of SMA where targeting cytokines would be a potential new supportive therapy for SMA patients.