IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing α-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression from CD4+ T cells drives α-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFNγ expression may be a potential disease modifying therapeutic strategy for MSA.

Disease mechanisms as subtypes: Inflammation in Parkinson disease and related disorders.

Neuroinflammation is a core feature of Parkinson disease (PD) and related disorders. Inflammation is detectable early in PD and persists throughout the disease state. Both the innate and the adaptive arms of the immune system are engaged in both human PD as well as in animal models of the disease. The upstream causes of PD are likely multiple and complex, which makes targeting of disease-modifying therapies based on etiological factors difficult. Inflammation is a broadly shared common mechanism and likely makes an important contribution to progression in most patients with manifest symptoms. Development of treatments targeting neuroinflammation in PD will require an understanding of the specific immune mechanisms which are active, their relative effects on both injury and neurorestoration, as well as the role of key variables likely to modulate the immune response: age, sex, the nature of the proteinopathies present, and the presence of copathologies. Studies characterizing the specific state of immune response in individuals and groups of people affected by PD will be essential to the development of targeted disease-modifying immunotherapies.

Assessing the Association of Mitochondrial Function and Inflammasome Activation in Murine Macrophages Exposed to Select Mitotoxic Tri-Organotin Compounds.

BACKGROUND: Mitochondrial function is implicated as a target of environmental toxicants and found in disease or injury models, contributing to acute and chronic inflammation. One mechanism by which mitochondrial damage can propagate inflammation is via activation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing receptor (NLRP)3 inflammasome, a protein complex that processes mature interleukin (IL)-1ß. IL-1ß plays an important role in the innate immune response and dysregulation is associated with autoinflammatory disorders. OBJECTIVE: The objective was to evaluate whether mitochondrial toxicants recruit inflammasome activation and IL-1ß processing. METHOD: Murine macrophages (RAW 264.7) exposed to tri-organotins (triethyltin bromide (TETBr), trimethyltin hydroxide (TMTOH), triphenyltin hydroxide (TPTOH), bis(tributyltin)oxide) [Bis(TBT)Ox] were examined for pro-inflammatory cytokine induction. TMTOH and TETBr were examined in RAW 264.7 and bone marrow-derived macrophages for mitochondrial bioenergetics, reactive oxygen species (ROS) production, and inflammasome activation via visualization of aggregate formation, caspase-1 flow cytometry, IL-1ß enzyme-linked immunosorbent assay and Western blots, and microRNA (miRNA) and mRNA arrays. RESULTS: TETBr and TMTOH induced inflammasome aggregate formation and IL-1ß release in lipopolysaccharide (LPS)-primed macrophages. Mitochondrial bioenergetics and mitochondrial ROS were suppressed. Il1a and Il1b induction with LPS or LPS+ATP challenge was diminished. Differential miRNA and mRNA profiles were observed. Lower miR-151-3p targeted cyclic adenosine monophosphate (cAMP)-mediated and AMP-activated protein kinase signaling pathways; higher miR-6909-5p, miR-7044-5p, and miR-7686-5p targeted Wnt beta-catenin signaling, retinoic acid receptor activation, apoptosis, signal transducer and activator of transcription 3, IL-22, IL-12, and IL-10 signaling. Functional enrichment analysis identified apoptosis and cell survival canonical pathways. CONCLUSION: Select mitotoxic tri-organotins disrupted murine macrophage transcriptional response to LPS, yet triggered inflammasome activation. The differential response pattern suggested unique functional changes in the inflammatory response that may translate to suppressed host defense or prolong inflammation. We posit a framework to examine immune cell effects of environmental mitotoxic compounds for adverse health outcomes. https://doi.org/10.1289/EHP8314.