The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis

Abstract

BackgroundMultiple sclerosis (MS) is an organ-specific autoimmune disease resulting in demyelinating plaques throughout the central nervous system. In MS, the exact role of microglia remains unknown. On one hand, they can present antigens, skew T cell responses, and upregulate the expression of pro-inflammatory molecules. On the other hand, microglia may express anti-inflammatory molecules and inhibit inflammation. Microglia express a wide variety of immune receptors such as nod-like receptors (NLRs). NLRs are intracellular receptors capable of regulating both innate and adaptive immune responses. Among NLRs, Nlrp12 is largely expressed in cells of myeloid origins. It plays a role in immune inflammatory responses by negatively regulating the nuclear factor-kappa B (NF-κB) pathway. Thus, we hypothesize that Nlrp12 suppresses inflammation and ameliorates the course of MS.MethodsWe used experimental autoimmune encephalomyelitis (EAE), a well-characterized mouse model of MS. EAE was induced in wild-type (WT) and Nlrp12−/− mice with myelin oligodendrocyte glycoprotein (MOG):complete Freud’s adjuvant (CFA). The spinal cords of healthy and immunized mice were extracted for immunofluorescence and pro-inflammatory gene analysis. Primary murine cortical microglia cell cultures of WT and Nlrp12−/− were prepared with cortices of 1-day-old pups. The cells were stimulated with lipopolysaccharide (LPS) and analyzed for the expression of pro-inflammatory genes as well as pro-inflammatory molecule secretions.ResultsOver the course of 9 weeks, the Nlrp12−/− mice demonstrated increased severity in the disease state, where they developed the disease earlier and reached significantly higher clinical scores compared to the WT mice. The spinal cords of immunized WT mice relative to healthy WT mice revealed a significant increase in Nlrp12 messenger ribonucleic acid (mRNA) expression at 1, 3, and 5 weeks post injection. A significant increase in the expression of pro-inflammatory genes Ccr5, Cox2, and IL-1β was found in the spinal cords of the Nlrp12−/− mice relative to the WT mice (P < 0.05). A significant increase in the level of gliosis was observed in the spinal cords of the Nlrp12−/− mice compared to the WT mice after 9 weeks of disease (P < 0.05). Primary Nlrp12−/− microglia cells demonstrated a significant increase in inducible nitric oxide synthase (iNOS) expression (P < 0.05) and secreted significantly (P < 0.05) more tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and nitric oxide (NO).ConclusionNlrp12 plays a protective role by suppressing inflammation during the development of EAE. The absence of Nlrp12 results in an increased inflammatory response.

Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

“…The authors demonstrated that Nlrp12 deficient mice are susceptible to dysbiosis and colitis and exhibit similar changes to those observed in EAE induction, with a loss of Lachnospiraceae family members and increases in the abundance of the Erysipelotrichaceae spp (Chen et al, 2017). Strikingly, Nlrp12 deficiency was also shown to exacerbate EAE (Gharagozloo et al, 2015, Lukens et al, 2015). It is possible that E2 treatment may therefore limit disease by similar mechanisms to Nlrp12, or indeed directly promote Nlrp12 expression.…”

Microbiome and morbid obesity increase pathogenic stimulus diversity

“…In encephalomyelitis NLRP12 negatively regulates the nuclear factor-kappa B (NF-kB) pathway suppressing inflammation [43].…”

Microglial NLRP3 Activity in Alzheimer's Disease

“…Microglial and other myeloid lineage cells express innate immune response-related receptors [14][15][16]. Antigen recognition in innate immune response is mediated by pattern recognition receptors, such as NOD-Like Receptor Family Receptors (NLRs), which recognize Pathogen-Associated Molecular Patterns (PAMPs) and Danger-Associated Molecular Patterns (DAMPs) [17].…”