β-Glucan-Induced Trained Immunity Protects against Leishmania braziliensis Infection: a Crucial Role for IL-32

Abstract

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.

Innate immune memory of tissue-resident macrophages and trained innate immunity: Re-vamping vaccine concept and strategies

“…Inducing both TII and adaptive immunity with a given vaccine strategy is expected to offer the best possible immune protection against the intended target pathogen while TII extends protection to a broad range of unrelated pathogens 84,85 . In this regard, keeping the current human vaccines and introducing new vaccines in human immunization programs with the known capability to induce TII will be of particular relevance to control pathogens of great health impact for which there has been a lack of effective human vaccines.…”

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

“…Apart from metabolic and epigenetic regulation, the induction of trained immunity is also modulated at the level of signaling mechanism. It has been reported that trained immunity induced by β-glucan in monocytes is critically dependent on cAMP-PKA, IL-1, and IL-32 signaling induction (50,52). Using pharmacological blockade or functional genomic analysis, it was shown that disruption of cAMP-PKA or IL-1 signaling inhibits training capacity of monocytes while enhancing IL-32 expression accelerates β-glucan-induced trained immunity (50,52).…”

“…It has been reported that trained immunity induced by β-glucan in monocytes is critically dependent on cAMP-PKA, IL-1, and IL-32 signaling induction (50,52). Using pharmacological blockade or functional genomic analysis, it was shown that disruption of cAMP-PKA or IL-1 signaling inhibits training capacity of monocytes while enhancing IL-32 expression accelerates β-glucan-induced trained immunity (50,52). Interestingly, IL-1 and IL-32 can promote the expression of each other in monocytes during β-glucan training, thus forming a self-reinforcing activating mechanism by which training effect of β-glucan can be enhanced (52).…”

“…Using pharmacological blockade or functional genomic analysis, it was shown that disruption of cAMP-PKA or IL-1 signaling inhibits training capacity of monocytes while enhancing IL-32 expression accelerates β-glucan-induced trained immunity (50,52). Interestingly, IL-1 and IL-32 can promote the expression of each other in monocytes during β-glucan training, thus forming a self-reinforcing activating mechanism by which training effect of β-glucan can be enhanced (52). Given the previously described role of IL-1 and IL-32 in metabolic regulation (33,53), it would be of potential interest to investigate whether they also contribute to metabolic adaptations essential for β-glucan-induced training of monocytes.…”

“…More recently, IL-32 was revealed as an additional important regulator for BCG-induced training in the bone marrow. Using transcriptomic approach, it was found that IL-32 regulates genes involved in cell metabolism, inflammatory immune response, transcriptional regulation, and signaling transduction in bone marrow progenitors, which are important for trained immunity induction (52). Notably, BCGinduced cell reprogramming in HSPCs has been demonstrated to be ultimately transmitted to their progeny cells, leading to epigenetically primed macrophages and a subsequent more protective effect against infection (32).…”