The Journal of immunology : official journal of the American Association of Immunologists
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Emerging evidence has demonstrated that CD4(+) T cells infiltrate into the substantia nigra (SN) in Parkinson's disease (PD) patients and in animal models of PD. SN-infiltrated CD4(+) T cells bearing inflammatory phenotypes promote microglial activation and strongly contribute to neurodegeneration of dopaminergic neurons. Importantly, altered expression of dopamine receptor D3 (D3R) in PBLs from PD patients has been correlated with disease severity. ⋯ Furthermore, RAG1 knockout mice, which are devoid of T cells and are resistant to MPTP-induced neurodegeneration, become susceptible to MPTP-induced loss of dopaminergic neurons when reconstituted with WT CD4(+) T cells but not when transferred with D3R-deficient CD4(+) T cells. In agreement, experiments analyzing activation and differentiation of CD4(+) T cells revealed that D3R favors both T cell activation and acquisition of the Th1 inflammatory phenotype. These findings indicate that D3R expressed on CD4(+) T cells plays a fundamental role in the physiopathology of MPTP-induced PD in a mouse model.
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Monocyte-derived macrophages (MDM) can polarize into different subsets depending on the environment and the activation signal to which they are submitted. Differentiation into macrophages allows HIV-1 strains to infect cells of the monocytic lineage. In this study, we show that culture of monocytes with a combination of IL-12 and IL-18 led to macrophage differentiation that was resistant to HIV-1 infection. ⋯ The HIV-1 restriction factor sterile α motif and HD domain-containing protein-1 (SAMHD1) was significantly overexpressed in IL-12/IL-18 MDM compared with M-CSF MDM, and degradation of SAMHD1 by RNA interference or viral-like particles carrying the lentiviral protein Vpx restored HIV-1 infectivity of IL-12/IL-18 MDM. SAMHD1 overexpression induced by IL-12/IL-18 was not dependent on IFN-γ. Thus, we conclude that IL-12 and IL-18 may contribute to the response against HIV-1 infection through the induction of restriction factors such as SAMHD1.
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Although reactive oxygen species (ROS) produced by NADPH oxidase are known to regulate inflammatory responses, the impact of ROS on intracellular signaling pathways is incompletely understood. In these studies, we treated wild-type (WT) and p47(phox)-deficient mice with LPS to investigate mechanisms by which NADPH oxidase regulates signaling through the NF-κB pathway. After intratracheal instillation of LPS, ROS generation was impaired in p47(phox)(-/-) mice, whereas these mice had increased neutrophilic alveolitis and greater lung injury compared with WT controls. ⋯ Treatment with the Ref-1-specific inhibitor E3330 or hydrogen peroxide inhibited LPS-induced NF-κB activation in p47(phox)(-/-)/HLL BMDMs but not in WT/HLL cells. Consistent with these findings, small interfering RNA against Ref-1 selectively reduced NF-κB activity in LPS-treated p47(phox)(-/-)/HLL BMDMs. Together, these results indicate that NADPH oxidase limits LPS-induced NF-κB transcriptional activity through regulation of intracellular redox state.
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Matrix metalloproteinase-8 (MMP-8) is a potent interstitial collagenase thought to be expressed mainly by polymorphonuclear neutrophils. To determine whether MMP-8 regulates lung inflammatory or fibrotic responses to bleomycin, we delivered bleomycin by the intratracheal route to wild-type (WT) versus Mmp-8(-/-) mice and quantified MMP-8 expression, and inflammation and fibrosis in the lung samples. Mmp-8 steady state mRNA and protein levels increase in whole lung and bronchoalveolar lavage samples when WT mice are treated with bleomycin. ⋯ Studies of bleomycin-treated Mmp-8 bone marrow chimeric mice show that both leukocytes and lung parenchymal cells are sources of profibrotic MMP-8 during bleomycin-mediated lung fibrosis. Thus, during bleomycin-mediated lung injury, MMP-8 dampens the lung acute inflammatory response, but promotes lung fibrosis by reducing lung levels of IP-10 and MIP-1α. These data indicate therapeutic strategies to reduce lung levels of MMP-8 may limit fibroproliferative responses to injury in the human lung.
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The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). TNF has been implicated in ALI pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. ⋯ Caspase-8 inhibition significantly improved AFC and oxygenation, whereas depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.