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Uncoupling of IL-6 signaling and LC3-associated phagocytosis (LAP) drives immunoparalysis during sepsis

ABSTRACT: Uncoupling of IL-6 signaling and LC3-associated phagocytosis (LAP) drives immunoparalysis during sepsis

PROVIDER: PRJNA728689 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14481400.fastq.gz	Fastqsanger.gz
	SRR14481500.fastq.gz	Fastqsanger.gz
	SRR14481401.fastq.gz	Fastqsanger.gz
	SRR14481501.fastq.gz	Fastqsanger.gz
	SRR14481402.fastq.gz	Fastqsanger.gz

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Uncoupling of IL-6 signaling and LC3-associated phagocytosis (LAP) drives immunoparalysis during sepsis

Project description:Immune deactivation of phagocytes is a central event in pathogenesis of sepsis that remains molecularly unexplored. In particular, how cytokine deregulation induced by sepsis compromises the microbicidal activity of phagocytes and results in secondary infections by opportunistic bacterial and fungal pathogens is incompletely understood. Herein, we identify a master regulatory role of cytokine signaling on LC3-associated phagocytosis (LAP), and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages.

2022-05-01 | GSE174183 | GEO

Regulation of myeloid function by LC3-associated phagocytosis promotes tumor immune tolerance

Project description:Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single cell RNAseq analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti-tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon the STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP.

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PDCD6 modulates LC3-associated phagocytosis-mediated antimicrobial defense by regulating lactate metabolism

Project description:LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.

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Adiponectin pathway activation dampens inflammation and enhances alveolar macrophage fungal killing via LC3-associated phagocytosis

Project description:Although innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus, potentially damaging inflammation must be controlled. Adiponectin (APN) is an anti-inflammatory adipokine, and we observed 100% mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN-/- AMs exhibited an inflammatory/M1 phenotype that was associated with decreased fungal killing and decreased activation of LC3-associated phagocytosis (LAP). Furthermore, AM treatment with the AdipoR agonist AdipoRon partially rescued deficient killing in APN-/- AMs that was dependent on both receptors. Our study identifies a novel role for APN in LC3-mediated killing of A.fumigatus.

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Project description:Mycobacterium tuberculosis’success as a pathogen comes from itsability to evade degradation by macrophages. Normally macro-phages clear microorganisms that activate pathogen-recognitionreceptors (PRRs) through a lysosomal-trafficking pathway called“LC3-associated phagocytosis”(LAP). AlthoughM.tuberculosisac-tivates numerous PRRs, for reasons that are poorly understoodLAP does not substantially contribute toM.tuberculosiscontrol.LAP depends upon reactive oxygen species (ROS) generated byNADPH oxidase, butM.tuberculosisfails to generate a robustoxidative response. Here, we show that CpsA, a LytR-CpsA-Psr(LCP) domain-containing protein, is required forM.tuberculosisto evade killing by NADPH oxidase and LAP. Unlike phagosomescontaining wild-type bacilli, phagosomes containing theΔcpsAmutant recruited NADPH oxidase, produced ROS, associated withLC3, and matured into antibacterial lysosomes. Moreover, CpsAwas sufficient to impair NADPH oxidase recruitment to fungal par-ticles that are normally cleared by LAP. Intracellular survival of theΔcpsAmutant was largely restored in macrophages missing LAPcomponents (Nox2,Rubicon,Beclin,Atg5,Atg7,orAtg16L1) butnot in macrophages defective in a related, canonical autophagypathway (Atg14,Ulk1,orcGAS). TheΔcpsAmutant was highlyimpaired in vivo, and its growth was partially restored in micedeficient in NADPH oxidase,Atg5,orAtg7, demonstrating thatCpsA makes a significant contribution to the resistance ofM.tu-berculosisto NADPH oxidase and LC3 trafficking in vivo. Overall,our findings reveal an essential role of CpsA in innate immuneevasion and suggest that LCP proteins have functions beyond theirpreviously known role in cell-wall metabolism.

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Project description:Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, but how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute to necrosis development in glioblastoma (GBM) by transferring myeloperoxidase (MPO)-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit neutrophil-induced tumor cell death by blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process involves LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model reduced necrosis formation and allowed tumor-bearing mice to survive longer. Therefore, this study revealed that the neutrophilic granule transfer involves LAP-mediated neutrophil internalization, which then triggers tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.

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