No abstract

Cryptococcus -associated immune reconstitution inflammatory syndrome (C-IRIS) is identified upon immune reconstitution in immunocompromised patients, who have previously contracted an infection of Cryptococcus neoformans ( Cn ). C-IRIS can be lethal but how the immune system triggers life-threatening outcomes in patients is still poorly understood. Here, we establish a mouse model for C-IRIS with Cn serotype A strain H99, which is highly virulent and the most intensively studied. C-IRIS in mice is induced by the adoptive transfer of CD4 + T cells in immunocompromised Rag1 -deficient mice infected with a low inoculum of Cn. The mice with C-IRIS exhibit symptoms which mimic clinical presentations of C-IRIS. This C-IRIS model is Th1-dependent and shows host mortality. This model is characterized with minimal lung injury, but infiltration of Th1 cells in the brain. C-IRIS mice also exhibited brain swelling with resemblance to edema and upregulation of aquaporin-4, a critical protein that regulates water flux in the brain in a Th1-dependent fashion. Our C-IRIS model may be used to advance our understanding of the paradoxical inflammatory phenomenon of C-IRIS in the context of neuroinflammation.

The AP-1 factor, basic leucine zipper transcription factor, ATF-like (BATF) is important for CD4+ T-helper (Th) 17, Th9 and follicular T helper (Tfh) cell development. However, its precise role in Th2 differentiation and function remains unclear, and the necessity of BATF in non-allergic settings of type-2 immunity has not been explored. Here, we show that in response to parasitic helminths, Batf−/− mice are unable to generate both Tfh and Th2 cells. As a consequence, Batf−/− mice fail to establish productive type-2 immunity during primary and secondary infection. Batf−/− CD4+ T cells do not achieve type-2 cytokine competency, which implies that BATF plays a key role in the regulation of interleukin(IL)-4 and IL-13. In contrast to Th17 and Th9 cell subsets where BATF binds directly to promoter and enhancer regions to regulate cytokine expression, our results show that BATF is significantly enriched at Rad50 hypersensitivity sites (RHS) 6 and 7 of the locus control region (LCR) relative to AP-1 sites surrounding type-2 cytokine loci in Th2 cells. Indeed, Batf−/− CD4+ T cells do not obtain permissive epigenetic modifications within the Th2 locus, which have been linked to RHS6 and RHS7 function. In sum, these findings reveal BATF as a central modulator of peripheral and humoral hallmarks of type-2 immunity, and begin to elucidate a novel mechanism by which BATF regulates type-2 cytokine production through its modification of the Th2 LCR.

No abstract

Pattern recognition receptors (PRRs) coordinate the innate immune response and have a significant role in the development of multiple sclerosis (MS). Accumulating evidence has identified both pathogenic and protective functions of PRR signaling in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Additionally, evidence for PRR signaling in non-immune cells and PRR responses to host-derived endogenous ligands has also revealed new pathways controlling the development of CNS autoimmunity. Many PRRs remain uncharacterized in MS and EAE, and understanding the distinct triggers and functions of PRR signaling in CNS autoimmunity requires further investigation. In this brief review, we discuss the diverse pathogenic and protective functions of PRRs in MS and EAE, and highlight major avenues for future research.

Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remains unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1β in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We found that this peptide (ANXA1sp) inhibited postoperative NLRP3 inflammasome activation and prevented microglial activation in the hippocampus, reducing PND-like memory deficits. Together our results reveal a previously under-recognized role of hippocampal ANXA1 and NLRP3 inflammasome dysregulation in triggering postoperative neuroinflammation, offering a new target for advancing treatment of PNDs through the resolution of inflammation.

Purpose of Review Despite the increasing number of clinical reports on immune reconstitution inflammatory syndrome (IRIS), mechanistic understanding of IRIS is still largely limited. The main focus of this review is to summarize animal studies, which were performed to better understand the cellular and molecular mechanisms underlying the pathology of IRIS. Recent Findings Three IRIS animal models have been reported. They are Mycobacterial IRIS (M-IRIS), cryptococcal IRIS (C-IRIS) and Pneumocystis-IRIS. M-IRIS animal model suggested that, rather than lymphopenia itself, the failure to clear the pathogen by T cells results in excessive priming of the innate immune system. If this happens before T cell reconstitution, hosts likely suffer IRIS upon T cell reconstitution. Interestingly, T cells specific to self-antigens, not only pathogen-specific, could drive IRIS as well. Summary The mechanism to develop IRIS is quite complicated, including multiple layers of host immune responses; the innate immune system that detects pathogens and prime host immunity, and the adaptive immune system that is reconstituted but hyper-activated particularly through CD4+ T cells. Animal models of IRIS, although there are still small numbers of studies available, have already provided significant insights on the mechanistic understanding of IRIS.

Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.