Probes for INS

Bacterial lipoproteins are an often-underappreciated class of microbe-associated molecular patterns with potent immunomodulatory activity. We previously reported that vaccination of BALB/c mice with Mycoplasma pneumoniae (Mp) lipid-associated membrane proteins (LAMPs) resulted in lipoprotein-dependent vaccine enhanced disease after challenge with virulent Mp, though the immune responses underpinning this phenomenon remain poorly understood. Herein, we report that lipoprotein-induced VED in a mouse model is associated with elevated inflammatory cytokines TNF-α, IL-1β, IL-6, IL-17A, and KC in lung lavage fluid and with suppurative pneumonia marked by exuberant neutrophilia in the pulmonary parenchyma. Whole-lung-digest flow cytometry and RNAScope analysis identified multiple cellular sources for IL-17A, and the numbers of IL-17A producing cells were increased in LAMPs-vaccinated/Mp-challenged animals compared to controls. Specific IL-17A or neutrophil depletion reduced disease severity in our VED model-indicating that Mp lipoproteins induce VED in an IL-17A-dependent manner and through exuberant neutrophil recruitment. IL-17A neutralization reduced levels of TNF-α, IL-1β, IL-6, and KC, indicating that IL-17A preceded other inflammatory cytokines. Surprisingly, we found that IL-17A neutralization impaired bacterial clearance, while neutrophil depletion improved it-indicating that, while IL-17A appears to confer both maladaptive and protective responses, neutrophils play an entirely maladaptive role in VED. Given that lipoproteins are found in virtually all bacteria, the potential for lipoprotein-mediated maladaptive inflammatory responses should be taken into consideration when developing vaccines against bacterial pathogens.

The field of cannabinoid research has been receiving ever-growing interest. Ongoing debates worldwide about the legislation of medical cannabis further motivates research into cannabinoid function within the central nervous system (CNS). To date, two well-characterized cannabinoid receptors exist. While most research has investigated Cb1 receptors (Cb1Rs), Cb2 receptors (Cb2Rs) in the brain have started to attract considerable interest in recent years. With indisputable evidence showing the wide-distribution of Cb2Rs in the brain of different species, they are no longer considered just peripheral receptors. However, in contrast to Cb1Rs, the functionality of central Cb2Rs remains largely unexplored. Here we review recent studies on hippocampal Cb2Rs. While conflicting results about their function have been reported, we have made significant progress in understanding the involvement of Cb2Rs in modulating cellular properties and network excitability. Moreover, Cb2Rs have been shown to be expressed in different subregions of the hippocampus, challenging our prior understanding of the endocannabinoid system. Although more insight into their functional roles is necessary, we propose that targeting hippocampal Cb2Rs may offer novel therapies for diseases related to memory and adult neurogenesis deficits.

Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention. Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases. Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an anti-inflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds. This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs. Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.

Cocaine use disorder (CUD) is a significant public health issue that generates substantial personal, familial, and economic burdens. Still, there are no FDA-approved pharmacotherapies for CUD. Cocaine-dependent individuals report anxiety during withdrawal, and alleviation of anxiety and other negative affective states may be critical for maintaining drug abstinence. However, the neurobiological mechanisms underlying abstinence-related anxiety in humans or anxiety-like behavior in rodents are not fully understood. This review summarizes investigations regarding anxiety-like behavior in mice and rats undergoing cocaine abstinence, as assessed using four of the most common anxiety-related assays: the elevated plus (or its derivative, the elevated zero) maze, open field test, light-dark transition test, and defensive burying task. We first summarize available evidence that cocaine abstinence generates anxiety-like behavior that persists throughout protracted abstinence. Then, we examine investigations concerning neuropeptide, neurotransmitter, and neuromodulator systems in cocaine abstinence-induced anxiety-like behavior. Throughout, we discuss how differences in sex, rodent strain, cocaine dose and dosing strategy, and abstinence duration interact to generate anxiety-like behavior.

Cumulative evidence has pointed out cannabinoid CB2 receptors (CB2r) as a potential therapeutic key target for treating alcohol use disorder (AUD). This review provides the most relevant results obtained from rodent and human studies, including an integrative section focused on the involvement of CB2r in the neurobiology of alcohol addiction. A literature search was conducted using the electronic databases Medline and Scopus for articles. The search strategy was as follows: “Receptor, Cannabinoid, CB2” AND “Alcohol-Related Disorders” AND “human/or patients”; “Receptor, Cannabinoid, CB2” AND “Alcohol” OR “Ethanol” AND “rodents/or mice/or rats”. Pharmacological approaches demonstrated that the activation or blockade of CB2r modulated different alcohol-addictive behaviors. Rodent models of alcoholism revealed significant alterations of CB2r in brain areas of the reward system. In addition, mice lacking CB2r (CB2KO) show increased alcohol consumption, motivation, and relapse alterations. It has been stressed that the potential neurobiological mechanisms underlying their behavioral effects involve critical elements of the alcohol reward system. Interestingly, recent postmortem studies showed CNR2 alterations in brain areas of alcoholic patients. Moreover, although the number of studies is limited, the results revealed an association between some genetic alterations of the CNR2 and an increased risk for developing AUD. This review provides evidence that CB2r may play a role in alcohol addiction. Clinical studies are necessary to figure out whether CB2r ligands may prove useful for the treatment of AUD in humans.

Cutaneous leishmaniasis is a parasitic infection that causes significant maternal morbidity, and even fetal mortality, during pregnancy, yet there are limited therapeutic options. Here, we report a case of leishmaniasis in a pregnant immigrant with exuberant mucocutaneous lesions with favorable response to liposomal amphotericin B.