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Nonredundancy of IL-1α and IL-1β is defined by distinct regulation of tissues orchestrating resistance versus tolerance to infection.

ABSTRACT: Interleukin-1α (IL-1α) and IL-1β are inflammatory cytokines with important roles in health and disease. They trigger the same receptor and elicit comparable cellular responses but, for poorly understood reasons, are not redundant in vivo. Here, we decoupled IL-1α and IL-1β functions that drive protective responses against invasive infection with group A Streptococcus. IL-1β was essential for pathogen clearance, hence resistance to infection, by inducing granulocyte colony-stimulating factor at the infection site and establishing emergency granulopoiesis. In contrast, IL-1α governed reprogramming of liver metabolic pathways associated with tolerance to infection. The IL-1α-dominated hepatic regulation corresponded to high IL-1α levels in the liver during infection. Conversely, IL-1β was critical for the regulation of the spleen transcriptome, which correlated with ample IL-1β expression in this tissue. The results identify distinct and organ-specific roles of IL-1α versus IL-1β and implicate spatial restriction of their expression and bioavailability during infection as the underlying mechanism.

SUBMITTER: Eislmayr K

PROVIDER: S-EPMC8890706 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Nonredundancy of IL-1α and IL-1β is defined by distinct regulation of tissues orchestrating resistance versus tolerance to infection.

Eislmayr Kevin K Bestehorn Annika A Morelli Luisa L Borroni Martina M Vande Walle Lieselotte L Lamkanfi Mohamed M Kovarik Pavel P

Science advances 20220302 9

Interleukin-1α (IL-1α) and IL-1β are inflammatory cytokines with important roles in health and disease. They trigger the same receptor and elicit comparable cellular responses but, for poorly understood reasons, are not redundant in vivo. Here, we decoupled IL-1α and IL-1β functions that drive protective responses against invasive infection with group A <i>Streptococcus</i>. IL-1β was essential for pathogen clearance, hence resistance to infection, by inducing granulocyte colony-stimulating fact ...[more]

PMID: 35235356

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Project description:Interleukin-1 (IL-1) is a major "alarm" upstream pro-inflammatory cytokine that also affects immunity and hematopoiesis by inducing cytokine cascades. In the tumor arena, IL-1 is produced by malignant or microenvironmental cells. As a pleiotropic cytokine, IL-1 is involved in tumorigenesis and tumor invasiveness but also in the control of anti-tumor immunity. IL-1α and IL-1β are the major agonists of IL-1, while IL-1Ra is a physiological inhibitor of pre-formed IL-1. In their secreted form, IL-1α and IL-1β bind to the same receptors and induce the same biological functions, but IL-1α and IL-1β differ in their compartmentalization within the producing cell or the microenvironment. IL-1β is only active in its processed, secreted form, and mediates inflammation, which promotes carcinogenesis, tumor invasiveness, and immunosuppression, whereas IL-1α is mainly cell-associated and in the tumor context, when expressed on the cell membrane, it stimulates anti-tumor cell immunity manifested by tumor regression. In the tumor milieu, extracellular levels of IL-1α are usually low and do not stimulate broad inflammation that promotes progression. Immunosuppression induced by IL-1β in the tumor microenvironment, mainly through MDSC induction, usually inhibits or masks anti-tumor cell immunity induced by cell-associated IL-1α. However, in different tumor systems, redundant or unique patterns of IL-1α and IL-1β expression and function have been observed. Recent breakthroughs in inflammasome biology and IL-1β processing/secretion have spurred the development of novel anti-IL-1 agents, which are being used in clinical trials in patients with diverse inflammatory diseases. Better understanding of the integrative role of IL-1α and IL-1β in distinct malignancies will facilitate the application of novel IL-1 modulation approaches at the bedside, in cancer patients with minimal residual disease (MRD), as an adjunct to conventional approaches to reduce the tumor burden.

Dataset Information

Nonredundancy of IL-1α and IL-1β is defined by distinct regulation of tissues orchestrating resistance versus tolerance to infection.

Publications

Nonredundancy of IL-1α and IL-1β is defined by distinct regulation of tissues orchestrating resistance versus tolerance to infection.

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