Biology subjects

Michmerhuizen, B. C.

Publications and source records attributed to Michmerhuizen, B. C..

3 recordsLinked to original sources

bioRxiv2024

Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection

Fine-tuned inflammation during infection enables pathogen clearance while minimizing host damage. Inflammation regulation depends on macrophage metabolic plasticity, yet coordination of metabolic and inflammatory programs is underappreciated. Here we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. In macrophages, staggered Toll-like receptor and type I IFN signaling permitted a transient respiratory burst followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. OXPHOS disruption promoted type I IFN, suppressing other pro-inflammatory cytokines, notably IL-{beta}. iNOS expression peaked at 24h post-infection, followed by lactate-driven iNOS repression via histone lactylation. In contrast, type I IFN pre-conditioning sustained infection-induced iNOS expression and amplified type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN led to elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/575104v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@977b1eorg.highwire.dtl.DTLVardef@1142c6corg.highwire.dtl.DTLVardef@170776borg.highwire.dtl.DTLVardef@b02c2f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Non-canonical activation of IRE1α during Candida albicans infection enhances macrophage fungicidal activity

While the canonical function of IRE1 is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1, which modulates innate immunity and infection outcomes. However, how infection activates IRE1 and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1, but it is unclear whether this depends on protein misfolding. Here, we report that a common and deadly fungal pathogen, Candida albicans, activates macrophage IRE1 through C-type lectin receptor signaling, reinforcing a role for IRE1 as a central regulator of host responses to infection by a broad range of pathogens. This activation did not depend on protein misfolding in response to C. albicans infection. Moreover, lipopolysaccharide treatment was also able to activate IRE1 prior to protein misfolding, suggesting that pathogen-mediated activation of IRE1 occurs through non-canonical mechanisms. During C. albicans infection, we observed that IRE1 activity promotes phagolysosomal fusion that supports the fungicidal activity of macrophages. Consequently, macrophages lacking IRE1 activity displayed inefficient phagosome maturation, enabling C. albicans to lyse the phagosome, evade fungal killing, and drive aberrant inflammatory cytokine production. Mechanistically, we show that IRE1 activity supports phagosomal calcium flux after phagocytosis of C. albicans, which is crucial for phagosome maturation. Importantly, deletion of IRE1 activity decreased the fungicidal activity of phagocytes in vivo during systemic C. albicans infection. Together, these data provide mechanistic insight for the non-canonical activation of IRE1 during infection, and reveal central roles for IRE1 in macrophage antifungal responses.

molecular biology↗

bioRxiv2022

Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II assembly and stability

Macrophage metabolic plasticity enables repurposing of electron transport from energy generation to inflammation and host defense. Altered Respiratory Complex II function has been implicated in cancer, diabetes and inflammation but regulatory mechanisms are incompletely understood. Here we show that macrophage inflammatory activation triggers Complex II disassembly and succinate dehydrogenase-B subunit loss through sequestration and mitophagy. Mitochondrial fission was required for lipopolysaccharide-stimulated succinate dehydrogenase-B degradation but not sequestration. We hypothesized that this Complex II regulatory mechanism might be coordinated by the mitochondrial phospholipid cardiolipin. Cardiolipin synthase knockdown prevented lipopolysaccharide-induced metabolic remodeling and Complex II disassembly, sequestration and degradation. Cardiolipin-depleted macrophages were defective in lipopolysaccharide-induced pro-inflammatory cytokine production, a phenotype partially rescued by Complex II inhibition. Thus, cardiolipin acts as a critical organizer of inflammatory metabolic remodeling.

immunology↗