ABSTRACT
The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.
Subject(s)
Acute Kidney Injury/pathology , Toll-Like Receptor 4/metabolism , Acute Kidney Injury/metabolism , Animals , Apoptosis , Creatinine/blood , Disease Models, Animal , Fibrosis , Kidney/innervation , Kidney/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microvessels/pathology , Signal Transduction , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/geneticsABSTRACT
Our knowledge about the meningeal immune system has recently burgeoned, particularly our understanding of how innate and adaptive effector cells are mobilized to meet brain challenges. However, information on how meningeal immunocytes guard brain homeostasis in healthy individuals remains sparse. This study highlights the heterogeneous and polyfunctional regulatory-T (Treg) cell compartment in the meninges. A Treg subtype specialized in controlling Th1-cell responses and another known to control responses in B-cell follicles were substantial components of this compartment, foretelling that punctual Treg-cell ablation rapidly unleashed interferon-gamma production by meningeal lymphocytes, unlocked their access to the brain parenchyma, and altered meningeal B-cell profiles. Distally, the hippocampus assumed a reactive state, with morphological and transcriptional changes in multiple glial-cell types; within the dentate gyrus, neural stem cells showed exacerbated death and desisted from further differentiation, associated with inhibition of spatial-reference memory. Thus, meningeal Treg cells are a multifaceted bulwark to brain homeostasis at steady-state. One sentence summary: A distinct population of regulatory T cells in the murine meninges safeguards homeostasis by keeping local interferon-γ-producing lymphocytes in check, thereby preventing their invasion of the parenchyma, activation of hippocampal glial cells, death of neural stem cells, and memory decay.
ABSTRACT
Listeria monocytogenes is an intracellular pathogen responsible for listeriosis, a foodborne disease that can lead to life-threatening meningitis. The 2011 L. monocytogenes cantaloupe outbreak was among the deadliest foodborne outbreaks in the United States. We conducted in vitro and in vivo infection analyses to determine whether strains LS741 and LS743, two clinical isolates from the cantaloupe outbreak, differ significantly from the common laboratory strain 10403S. We showed that LS741 and LS743 exhibited increased virulence, characterized by higher colonization of the brain and other organs in mice. Assessment of cellular immune responses to known CD8+ T cell antigens was comparable between all strains. However, pre-existing immunity to 10403S did not confer protection in the brain against challenge with LS741. These studies provide insights into the pathogenesis of clinical isolates linked to the 2011 cantaloupe outbreak and also indicate that currently utilized laboratory strains are imperfect models for studying L. monocytogenes pathogenesis.