The “Dialogue” Between Central and Peripheral Immunity After Ischemic Stroke: Focus on Spleen

The immune response generated by the body after the incidence of ischemic stroke, runs through the comprehensive process of aftermath. During this process of ischemic stroke, the central neuroinflammation and peripheral immune response seriously affect the prognosis of patients, which has been the focus of research in recent years. As this research scenario progressed, the “dialogue” between central nervous inflammation and peripheral immune response after ischemic stroke has become more closely related. It’s worth noting that the spleen, as an important peripheral immune organ, plays a pivotal role in this dialogue. Multiple mechanisms have previously been reported for brain-spleen crosstalk after ischemic stroke. Further, neuroinflammation in the brain can affect the peripheral immune state by activating/inhibiting spleen function. However, the activation of the peripheral immune inflammatory response can work reversibly in the spleen. It further affects intracerebral neuroinflammation through the injured blood-brain barrier. Therefore, paying close attention to the role of spleen as the pivot between central and peripheral immunity in ischemic stroke may help to provide a new target for immune intervention in the treatment of ischemic stroke. In the present review, we reviewed the important role of spleen in central neuroinflammation and peripheral immune response after ischemic stroke. We summarized the relevant studies and reports on spleen as the target of immune intervention which can provide new ideas for the clinical treatment of ischemic stroke.

Revisiting the Immunological Aspects of Temozolomide Considering the Genetic Landscape and the Immune Microenvironment Composition of Glioblastoma

The microenvironment (ME) plays a critical role in causing glioblastoma (GBM) to be a moving and incurable target. The main features governing the interaction between cancer cells and the ME include dependency, promotion, and in rare cases, even competition. In the original Stupp protocol, the alkylating agent temozolomide (TMZ) is the first-line chemotherapy drug to treat GBM, and it is broadly used together or after radiotherapy. Some studies have described TMZ as an adjuvant to other therapeutic approaches including immunotherapy because of its ability to induce an immunogenic death of cancer cells. TMZ also exerts immunomodulatory effects on the tumor and immune ME. These findings support the coexistence of two circuits, i.e., one that subverts local immunosuppressive mechanisms and another that exerts a harmful influence on the peripheral immune response. A bias toward the latter can drive the failure of treatments based on the combination of chemotherapy and immunotherapy approaches. In this review, we will reanalyze how intrinsic and acquired resistance to TMZ impacts the immunomodulatory effects previously described by way of inducing a functional alteration of local immune cells and promoting immunosuppression and how different components of the immune ME, with particular attention to tumor-associated macrophages and microglia, can cause TMZ resistance to circumvent potential local immunogenic mechanisms.

Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza, and other community-acquired pneumonia

The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by a general lack of relevant disease controls. The scarcity of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in peripheral blood mononuclear cells from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach, we describe shared and diverging transcriptional and phenotypic patterns—including increased levels of type I interferon-stimulated natural killer cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups—and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia.

Peripheral sTREM2-related inflammatory activity alterations in early stage Alzheimer's disease

Alzheimer's disease (AD) has been linked to multiple immune system genetic variants, implicating potential broad alterations in inflammatory profiles in the disease. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble TREM2 isoform (sTREM2) is elevated in cerebrospinal fluid in the early stages of AD suggesting it may be a biomarker of progressive alterations in immune response to AD-related pathology. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between plasma sTREM2 and the altered peripheral immune response in AD. The objective of this exploratory study was to examine the relationship between sTREM2 and inflammatory activity in human participants defined by clinically characterized cognitive symptoms and groups defined by the cerebrospinal fluid biomarkers amyloid beta, phosphorylated tau, and neurodegeneration (NIA-AA Research Framework: "ATN continuum".) The hypothesis of this exploratory study was that sTREM2 related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across disease groups and ATN categories that implicates peripheral sTREM2 related inflammatory activity as altered in the early stages of AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost as disease progressed, and fractalkine, IL-5 and IL-17A were decreased in AD. These preliminary data provide important support to the hypothesis that sTREM2-related inflammatory activity is a stage-specific biomarker of AD progression, providing the groundwork for future studies and therapeutic strategies.

Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.

Metabolomics Monitoring of Treatment Response to Brain Tumor Immunotherapy

Immunotherapy has revolutionized care for many solid tissue malignancies, and is being investigated for efficacy in the treatment of malignant brain tumors. Identifying a non-invasive monitoring technique such as metabolomics monitoring to predict patient response to immunotherapy has the potential to simplify treatment decision-making and to ensure therapy is tailored based on early patient response. Metabolomic analysis of peripheral immune response is feasible due to large metabolic shifts that immune cells undergo when activated. The utility of this approach is under investigation. In this review, we discuss the metabolic changes induced during activation of an immune response, and the role of metabolic profiling to monitor immune responses in the context of immunotherapy for malignant brain tumors. This review provides original insights into how metabolomics monitoring could have an important impact in the field of tumor immunotherapy if achievable.

Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.

Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza and other community-acquired pneumonia.

The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by methodological heterogeneity and a lack of relevant disease controls. The absence of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in PBMCs from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach we describe shared and diverging transcriptional and phenotypic patterns – including increased levels of type I interferon stimulated NK cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups – and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia.