American tegumentary leishmaniasis is a vectorborne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Gué rin (BCG) vaccination via a process called trained immunity, conferring nonspecific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component b-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32g in the trained phenotype induced by b-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.
Interleukin 32 (IL-32) is a proinflammatory cytokine, expressed as 9 distinct isoforms. The most active isoform is the predominantly intracellular-functioning IL-32γ. Involvement of IL-32 in infectious diseases is increasingly being appreciated. Production of IL-32 promotes pathways that serve to control bacterial infection, especially those caused by mycobacteria. A similar role for this cytokine is observed in the cellular response to viral infections. In addition to its protective effects against microorganisms, IL-32 is involved in immunopathogenesis of some infectious diseases. In parasitic diseases, it has been demonstrated that this cytokine is induced by Leishmania infection. In this review, we summarize the present data on the role of IL-32 in infectious diseases, highlighting this cytokine as new target for control of infections.
BackgroundInterleukin-32 (IL-32) is expressed in lesions of patients with American Tegumentary Leishmaniasis (ATL), but its precise role in the disease remains unknown.Methodology/Principal findingsIn the present study, silencing and overexpression of IL-32 was performed in THP-1-derived macrophages infected with Leishmania (Viannia) braziliensis or L. (Leishmania) amazonensis to investigate the role of IL-32 in infection. We report that Leishmania species induces IL-32γ, and show that intracellular IL-32γ protein production is dependent on endogenous TNFα. Silencing or overexpression of IL-32 demonstrated that this cytokine is closely related to TNFα and IL-8. Remarkably, the infection index was augmented in the absence of IL-32 and decreased in cells overexpressing this cytokine. Mechanistically, these effects can be explained by nitric oxide cathelicidin and β-defensin 2 production regulated by IL-32.ConclusionsThus, endogenous IL-32 is a crucial cytokine involved in the host defense against Leishmania parasites.
COVID‐19 is a severe health problem in many countries and has altered day‐to‐day life in the whole world. This infection is caused by the SARS‐CoV‐2 virus, and depending on age, sex and health status of the patient, it can present with variety of clinical symptoms such as mild infection, a very severe form or even asymptomatic course of the disease. Similarly to other viruses, innate immune response plays a vital role in protection against COVID‐19. However, dysregulation of innate immunity could have a significant influence on the severity of the disease. Despite various efforts, there is no effective vaccine against the disease so far. Recent data have demonstrated that the Bacillus Calmette–Guérin (BCG) vaccine could reduce disease severity and the burden of several infectious diseases in addition to targeting its primary focus tuberculosis. There is growing evidence for the concept of beneficial non‐specific boosting of immune responses by BCG or other microbial compounds termed trained immunity, which may protect against COVID‐19. In this manuscript, we review data on how the development of innate immune memory due to microbial compounds specifically BCG can result in protection against SARS‐CoV‐2 infection. We also discuss possible mechanisms, challenges and perspectives of using innate immunity as an approach to reduce COVID‐19 severity.
Highlights d Set7 regulates enhanced cytokine production in trained immunity in vitro d Set7 knockout mice are unable to mount trained immunity against endotoxin challenge d Set7 modulates cellular respiration in b-glucan-trained macrophages d Set7-dependent histone methylation regulates MDH2 and SDHB in trained cells
Patients with rheumatoid arthritis (RA) are at higher risk of developing cardiovascular diseases (CVD). Interleukin (IL)-32 has previously been shown to be involved in the pathogenesis of RA and might be linked to the development of atherosclerosis. However, the exact mechanism linking IL-32 to CVD still needs to be elucidated. The influence of a functional genetic variant of IL-32 on lipid profiles and CVD risk was therefore studied in whole blood from individuals from the NBS cohort and RA patients from 2 independent cohorts. Lipid profiles were matched to the specific IL-32 genotypes. Allelic distribution was similar in all three groups. Interestingly, significantly higher levels of high density lipoprotein cholesterol (HDLc) were observed in individuals from the NBS cohort and RA patients from the Nijmegen cohort homozygous for the C allele (p = 0.0141 and p = 0.0314 respectively). In contrast, the CC-genotype was associated with elevated low density lipoprotein cholesterol (LDLc) and total cholesterol (TC) in individuals at higher risk for CVD (plaque positive) (p = 0.0396; p = 0.0363 respectively). Our study shows a functional effect of a promoter single-nucleotide polymorphism (SNP) in IL32 on lipid profiles in RA patients and individuals, suggesting a possible protective role of this SNP against CVD.
Regulation of IL-32 in human primary liver cells, HepG2 and THP-1 cells strongly influences the mRNA expression of ABCA1, ABCG1, LXRα and apoA1 and affects intracellular lipid concentrations in the presence of endogenous IL-32. These data, for the first time, show an important role for IL32 in cholesterol homeostasis.
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