NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

Abstract

The NLRP3 inflammasome is a multiprotein complex consisting of three kinds of proteins, NLRP3, ASC, and pro-caspase-1, and plays a role in sensing pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, the mechanism by which the NLRP3 inflammasome induces EAE is not clear. In this study, we found that the NLRP3 inflammasome played a critical role in inducing T-helper cell migration into the CNS. To gain migratory ability, CD4 + T cells need to be primed by NLRP3 inflammasome-sufficient antigen-presenting cells to up-regulate chemotaxis-related proteins, such as osteopontin, CCR2, and CXCR6. In the presence of the NLRP3 inflammasome, dendritic cells and macrophages also induce chemotactic ability and up-regulate chemotaxis-related proteins, such as α4β1 integrin, CCL7, CCL8, and CXCL16. On the other hand, reduced Th17 cell population size in immunized Nlrp3 −/− and Asc −/− mice is not a determinative factor for their resistance to EAE. As currently applied in clinical interventions of MS, targeting immune cell migration molecules may be an effective approach in treating MS accompanied by NLRP3 inflammasome activation.

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

“…Opn is up-regulated in IBD (24)(25)(26)(27)(28)(29) and several other inflammatory conditions (16)(17)(18)(19)(20)(21)89). However, whether this upregulation can be attributed to specific cellular sources remains elusive.…”

“…However, whether this is a direct effect of Opn on DC subset recruitment is unknown. Opn itself can act as a chemotaxis molecule for DCs (20,37,88). Whether CD103 − DCs preferentially bear certain Opn receptors that eventually influence their MLN recruitment remains unknown.…”

“…Increased plasma Opn levels are related to the severity of CD inflammation (29), and certain Opn gene (Spp1) haplotypes are modifiers of CD susceptibility (31), indicating that Opn could be used as an IBD biomarker (27). In general, Opn affects DC biology during several inflammatory conditions (17)(18)(19)(20)(21)(32)(33)(34)(35)(36)(37) and could be a potential therapeutic target in IBD.…”

“…Opn is expressed by DCs and other immune cell types, such as lymphocytes, during autoimmune responses (16)(17)(18)(19)(20)(21)(22), and its expression by DCs during autoimmunity contributes to disease severity (17-19, 21, 23). In addition, Opn expression is highly up-regulated in intestinal immune and nonimmune cells and in the plasma of patients with CD and UC (24)(25)(26)(27)(28)(29), as well as in the colon and plasma of mice with experimental colitis (14,15,27,30).…”

Effect of ether glycerol lipids on interleukin-1β release and experimental autoimmune encephalomyelitis

“…There is also a strong prognostic relationship between IL-1β levels and disease progression and mutation of the Nlrp3 gene is associated with MS-like lesions (Compeyrot-Lacassagne et al 2009;Dodé, et al 2002). In addition, mice lacking the gene encoding NLRP3 (Nlrp3 -/-) develop significantly milder symptoms in an experimental autoimmune encephalomyelitis (EAE) model and exhibit a reduction in IFNγ-and IL-17-expressing TH cells in peripheral lymphoid tissues and the spinal cord (Gris et al 2010;Inoue et al 2012). IL-1β also induces activation of microglial cells, which stimulate Tlymphocytes with self-antigen during EAE development.…”