Cardiotoxicity caused by immune checkpoint inhibitors is one of the most severe and potentially fatal side effects. Hence it is crucial from a therapeutic standpoint to understand the underlying processes and devise countermeasures. This study sought to determine whether the SOCS3/JAK/STAT3 signaling pathway, which controls macrophage polarization, contributes to the cardiotoxicity caused by PD-1/PD-L1 inhibitors. The PD-1/PD-L1 inhibitor BMS-1 (10 mg/kg) was used to create a mouse model of immune checkpoint inhibitor-related cardiotoxicity, and hematoxylin and Masson's trichome tests were used to measure cardiomyocyte apoptosis and cardiotoxicity. The production of M1 factors (tumor necrosis factor α [TNF-α] and interleukin [IL]-1 b), as well as the blood levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB, and lactate dehydrogenase), were evaluated by ELISA. Echocardiography was used to assess the heart's health. The processes were investigated using flow cytometric analysis, real-time PCR, Western blot, and chromatin immunoprecipitation. We found that the PD-1/PD-L1 inhibitor BMS-1 dramatically reduced tumor weight while considerably impairing cardiac function in melanoma-induced tumor-bearing mice. At the gene and protein levels, it was found that levels of SOCS3, JAK, STAT3, and the inflammatory mediators IL-6 and TNF-α had all significantly decreased. Immune checkpoint inhibitor-induced cardiotoxicity may be linked to major changes in the SOCS3/JAK/STAT3 signaling pathway, as indicated by the knockdown of SOCS3, JAK, and STAT3. Finally, immune checkpoint inhibitor intervention demonstrated a large elevation of CD86+ and MHCII+ as well as a considerable increase in macrophages. These data suggest that the SOCS3/JAK/STAT3 signaling pathway, which controls macrophage polarization, may be linked to cardiotoxicity caused by PD-1/PD-L1 inhibitor therapy.
Copyright © 2025 Termedia.

Cytomegalovirus is a promising vaccine vector; however, mechanisms promoting CD4 T cell responses to challenge, by CMV as a vector, are unknown. The ability of MCMV to prolong immunity generated by short-lived malaria vaccine was tested. MCMV provided non-specific protection to challenge with Plasmodium and increased interleukin-12 (IL-12) and CD8α+ dendritic cell (DC) numbers through prolonged MCMV-dependent interferon gamma (IFN-γ) production. This late innate response to MCMV increased IL-12 upon challenge and increased the polyclonal CD4 effector T cell response to Plasmodium, protecting in an IL-12-dependent manner. Although Plasmodium-vaccine-induced protection decayed by d200, MCMV restored protection through IFN-γ. Mechanistically, protection depended on MCMV-induced-IFN-γ increasing CD8α+ DCs and IL-12p40. MCMV expressing a Plasmodium epitope increased parasite-specific CD4 effector and effector memory T cells persisting after malaria vaccination, both phenotypes reported to protect. Overall, enhanced innate cell status, a mechanism of heterologous protection by MCMV, led to a stronger T cell response to challenge.
© 2024 The Authors.

Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKβ and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.
© 2024. The Author(s).

Lupus nephritis (LN) is among the most common complication of systemic lupus erythematosus (SLE) with high mortality and morbidity. The analysis of LN kidney's local immune response through single-cell and spatial transcriptome enables the study of potential therapeutic targets.
By single cell sequencing and spatial transcriptome, we profile cells from LN kidney and normal kidney tissues to characterize cellular composition and elucidate the potential upstream monocyte/macrophage (Mono/MΦ) initiating the auto-immune response. After the high-throughput synergy screening, we performed the immunofluorescence to identify the specific cells in LN patients. The function experiments were finished by flow cytometry and Elisa.
By immunofluorescence and spatial transcriptome, we identified differential subsets of Mono/MΦ and demonstrated that they exhibit temporal expression of TIMP1, IL1B, SPP1 and APOE. With the function experiments, we found that the APOE+ Mono may be compensatorily increased in LN, and the capacity of antigen presenting was decreased with the overexpression of APOE. Furthermore, how do the LN-specific Mono/MΦ transport in and out the glomerulus to active the local immune response remains unclear. Our results showed that lymphangiogenesis occurred in LN kidneys but not in normal kidneys, suggesting the presence of a new lymphatic vessel may serve as a 'green channel' for LN-specific Mono/MΦ.
In LN, APOE+ Mono are compensatorily elevated, with decreased antigen presenting ability and reduced secretion of interferons. The lymphangiogenesis in LN prompts the trafficking of Mono/MΦ in LN kidney.
© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

The C-type lectin-related protein, Clr-f, encoded by Clec2h in the mouse NK gene complex (NKC), is a member of a family of immune regulatory lectins that guide immune responses at distinct tissues of the body. Clr-f is highly expressed in the kidney; however, its activity in this organ is unknown. To assess the requirement for Clr-f in kidney health and function, we generated a Clr-f-deficient mouse (Clr-f-/-) by targeted deletions in the Clec2h gene. Mice lacking Clr-f exhibited glomerular and tubular lesions, immunoglobulin and C3 complement protein renal deposits, and significant abdominal and ectopic lipid accumulation. Whole kidney transcriptional profile analysis of Clr-f-/- mice at 7, 13, and 24 weeks of age revealed a dynamic dysregulation in lipid metabolic processes, stress responses, and inflammatory mediators. Examination of the immune contribution to the pathologies of Clr-f-/- mouse kidneys identified elevated IL-12 and IFNγ in cells of the tubulointerstitium, and an infiltrating population of neutrophils and T and B lymphocytes. The presence of these insults in a Rag1-/-Clr-f-/- background reveals that Clr-f-/- mice are susceptible to a T and B lymphocyte-independent renal pathogenesis. Our data reveal a role for Clr-f in the maintenance of kidney immune and metabolic homeostasis.
© 2022. The Author(s).