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Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL-37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, here we show that the longest IL-37 isoform, IL-37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1β. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53-truncated form of IL-37, mimicking the cathepsin S–processed form of this cytokine, was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R −/− animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases.

Peer reviewed: True, Funder: Trinity College Dublin; FundRef: http://dx.doi.org/10.13039/501100001637, Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the 'classically activated' M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, 'alternatively activated' M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

Adjuvants can be incorporated into vaccines to enhance the magnitude and functionality of adaptive immune responses. In this issue of Immunity, Alameh et al. (2021) reveal that lipid nanoparticles, which are key components of effective SARS-CoV-2 mRNA vaccines, have broad adjuvant function, enhancing B cell responses and protective efficacy of protein-based subunit in addition to mRNA antigens.

Adjuvants are a miscellaneous range of molecules and materials that can enhance the magnitude, functionality, breadth and durability of immune responses. Despite the multiplicity of compounds with adjuvant properties, less than a dozen are in clinical use in vaccines against infectious diseases. While many factors have contributed to their slow development, among the major challenges are the high safety and efficacy standards set by current adjuvants in human vaccines and our limited understanding of how adjuvants mediate their effects. This review outlines why it is so difficult to elucidate their mechanism of action, highlights areas that require in-depth research and discusses recent advancements that are revitalising adjuvant development. It is hoped that a fuller understanding of adjuvant sensing, signalling and function will facilitate the design of vaccines that promote sustained protective immunity against challenging bacterial and viral pathogens.

Biocompatible and biodegradable biomaterials are used extensively in regenerative medicine and serve as a tool for tissue replacement, as a platform for regeneration of injured tissue, and as a vehicle for delivery of drugs. One of the key factors that must be addressed in developing successful biomaterial-based therapeutics is inflammation. Whilst inflammation is initially essential for wound healing; bringing about clearance of debris and infection, prolonged inflammation can result in delayed wound healing, rejection of the biomaterial, further tissue damage and increased scarring and fibrosis. In this context, the choice of biomaterial must be considered carefully to minimise further induction of inflammation. Here we address the ability of the biomaterials themselves to modulate inflammatory responses and outline how the physico-chemical properties of the materials impact on their pro and anti-inflammatory properties (Fig. 1).