Previous studies have demonstrated immunosuppressive and anti-inflammatory effects of nicotine, including in the experimental autoimmune encephalomyelitis (EAE) model in mice of some forms of multiple sclerosis (MS). Other studies using knock-out (KO) mice have implicated nicotinic acetylcholine (ACh) receptors containing Î±7, Î±9, or Î²2 subunits (Î±7*-, Î±9*- or Î²2*-nAChR) in different, disease exacerbating or disease-ameliorating processes. These outcomes are in harmony with gene expression analyses showing nAChR subunit mRNA in many classes of immune system cell types. Consistent with influences on disease status, predictable effects of nAChR subunit (and subtype) KO, or of nicotine exposure, are seen on immune cell numbers and distribution and on cytokine levels or other markers of immunity, inflammation, demyelination, and axonal degradation. Providing support for our hypotheses about distinctive roles for nAChR subtypes in EAE, here we have used direct and adoptive EAE induction and a nAChR subunit gene double knock-out (DKO) strategy. Immune cell expression of nAChR Î±9 subunits as protein is demonstrated by immunostaining of isolated CD4+, CD8+, CD11b+ and CD11c+ cells from wild-type (WT) mice, but not in cells from nAChR Î±9 subunit KO animals. Nicotine exposure is protective against directly-induced EAE in WT or Î±7/Î±9 DKO animals relative to effects seen in WT/vehicle-treated mice, but, remarkably, EAE is exacerbated in vehicle-treated Î±7/Î±9 DKO mice. Brain lesion volume and intracranial inflammatory activity similarly are higher in DKO/vehicle than in WT/vehicletreated animals, although nicotineâ€™s protective effects are seen in each instance. By contrast, in adoptive transfer studies, disease severity is attenuated and disease onset is delayed in recipients of splenocytes from WT animals treated with nicotine rather than with vehicle. Moreover, protection as seen in nicotine-treated WT animals is the same in recipients of splenocytes from nAChR Î±7/Î±9 DKO mice irrespective of their exposure to nicotine or vehicle. When combined with previous observations, these findings are consistent with disease exacerbation (or even induction) being mediated at least in part via Î±9*-nAChR in peripheral immune cells. They also suggest protective roles of central nervous system (CNS) Î±7*-nAChR. The results suggest that both Î±7*- and Î±9*-nAChR are potential targets of therapeutic ligands to modulate inflammation and autoimmunity.
Frontiers in Cellular Neuroscience
Digital Object Identifier (DOI)
Liu, Qiang; Whiteaker, Paul; Morley, Barbara J.; Shi, Fu Dong; and Lukas, Ronald J., "Distinctive Roles For Î±7*- And Î±9*-Nicotinic Acetylcholine Receptors In Inflammatory And Autoimmune Responses In The Murine Experimental Autoimmune Encephalomyelitis Model Of Multiple Sclerosis" (2017). Neurobiology. 208.