Earlier studies reported that a cell membrane protein Annexin A2 (AnxA2) plays multiple roles in the development, invasion and metastasis of cancer. Recent studies have demonstrated that AnxA2 also functions in immunity against infection, but the underlying mechanism remains largely elusive. Using a mouse infection model, we now reveal a crucial role of AnxA2 in host defense against Pseudomonas aeruginosa (Pa), as anxa2−/− mice manifested severe lung injury, systemic dissemination, and increased mortality compared to wild-type (WT) littermates. In addition, anxa2−/− mice exhibited elevated inflammatory cytokines (TNF-α, IL-6, IL-1β and IFN-γ), decreased bacterial clearance by macrophages, and increased superoxide release in the lung. We further identified an unexpected molecular interaction between AnxA2 and Fam13A (Family with sequence similarity 13, member A), which activated Rho GTPase. P. aeruginosa infection induced autophagosome formation by inhibiting Akt1 and mTOR. Our results indicate that AnxA2 regulates autophagy and thereby contributing to host immunity against bacteria through Akt1-mTOR-ULK1/2 signaling pathway.
Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM), which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3-methyladenine (3-MA) or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM. Both morphological and biological evidence demonstrated that Lyn delivered bacteria to lysosomes through xenophagy. TLR2 initiated the phagocytic process and activated Lyn following infection. Cytoskeletal trafficking proteins, such as Rab5 and Rab7, critically facilitated early phagosome formation, autophagosome maturation, and eventual autophagy-mediated bacterial degradation. These findings reveal that Lyn, TLR2 and Rab modulate autophagy related phagocytosis and augment bactericidal activity, which may offer insight into novel therapeutic strategies to control lung infection.
Loss of Atg7 switched binding of p-IκBα from Atg7 to Ub, resulting in increased ubiquitylation of p-IκBα and intensified inflammatory responses against K. pneumoniae. Our findings not only reveal a regulatory role of Atg7 in ubiquitylation of p-IκBα but also indicate potential therapeutic targets for K. pneumoniae control.
Introduction:Laparoscopic port site metastases are a rare but clinically important cause of biochemically recurrent prostate adenocarcinoma. C-11 choline, among other prostate-specific positron emission tomography (PET) radiotracers, has improved radiologist confidence in these otherwise difficult-to-detect sites of recurrence.Patient Concerns:A 62-year-old male presented with biochemically recurrent prostate adenocarcinoma after undergoing robotic-assisted radical prostatectomy 5 years earlier.Diagnosis:C-11 choline positron emission tomography/computed tomography (PET/CT) demonstrated a choline-avid soft tissue nodule associated with a laparoscopic port site in the right rectus abdominis muscle, with correlative findings on prior magnetic resonance imaging, and biopsy confirming a prostate adenocarcinoma metastasis.Interventions:The patient was initiated on chemohormonal therapy.Outcomes:His prostate-specific antigen (PSA) became undetectable following chemohormonal therapy. A follow-up C-11 choline PET/CT demonstrated complete resolution of prior abnormal radiotracer activity in the right rectus abdominis muscle.Lessons:Port site metastases in prostate adenocarcinoma are rare; however, those who treat prostate cancer patients should be aware of this phenomenon as the number of minimally invasive oncologic procedures increase. C-11 choline PET, among other prostate-specific PET probes, has become an important tool in evaluating patients with biochemically recurrent prostate adenocarcinoma, identifying site-specific metastases in a majority of patients.
A 43-year-old woman presented with an FDG-avid mediastinal Ewing sarcoma invading and nearly occluding the superior vena cava. Geographic increased FDG uptake in hepatic segment IVA was the only other site of nonphysiologic FDG activity. This focal activity was without an underlying mass, had atypical morphology for a hepatic metastasis, and correlated well with prior CT findings of abnormal segment IVA enhancement resulting from the recruitment of portocaval collaterals. In the correct setting, the F-FDG hepatic hot spot should be considered in the differential of a focal FDG-avid hepatic lesion in segment IVA.
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