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1. Exacerbated post‐infarct pathological myocardial remodelling in diabetes is associated with impaired autophagy and aggravated NLRP3 inflammasome activation

   https://doi.org/10.1002/ehf2.13754  

   Mao, Shuai ; Chen, Peipei ; Pan, Wenjun ; Gao, Lei ; Zhang, Minzhou ( December 2021 , ESC Heart Failure)

   Diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher mortality due to the more frequent development of subsequent pathological myocardial remodelling and concomitant functional deterioration. This study investigates the molecular pathways underlying accelerated cardiac remodelling in a well‐established mouse model of diabetes exposed to MI.

   Myocardial infarction in DM mice was established by ligating the left anterior descending coronary artery. Cardiac function was assessed by echocardiography. Myocardial hypertrophy and cardiac fibrosis were determined histologically 6 weeks post‐MI or sham operation. Autophagy, the NLRP3 inflammasome, and caspase‐1 were evaluated by western blotting or immunofluorescence. Echocardiographic imaging revealed significantly increased left ventricular dilation in parallel with increased mortality after MI in DM mice (53.33%) compared with control mice (26.67%,P < 0.05). Immunoblotting, electron microscopy, and immunofluorescence staining for LC3 and p62 indicated impaired autophagy in DM + MI mice compared with control mice (P < 0.05). Furthermore, defective autophagy was associated with increased NLRP3 inflammasome and caspase‐1 hyperactivation in DM + MI mouse cardiomyocytes (P < 0.05). Consistent with NLRP3 inflammasome and caspase‐I hyperactivation, cardiomyocyte death and IL‐1β and IL‐18 secretion were increased in DM + MI mice (P < 0.05). Importantly, the autophagy inducer and the NLRP3 inhibitor attenuated the cardiac remodelling of DM mice after MI.

   In summary, our results indicate that DM aggravates cardiac remodelling after MI through defective autophagy and associated exaggerated NLRP3 inflammasome activation, proinflammatory cytokine secretion, suggesting that restoring autophagy and inhibiting NLRP3 inflammasome activation may serve as novel targets for the prevention and treatment of post‐infarct remodelling in DM.

    

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2. Mediation of Cartilage Matrix Degeneration and Fibrillation by Decorin in Post‐traumatic Osteoarthritis

   https://doi.org/10.1002/art.41254  

   Li, Qing ; Han, Biao ; Wang, Chao ; Tong, Wei ; Wei, Yulong ; Tseng, Wei‐Ju ; Han, Li‐Hsin ; Liu, X. Sherry ; Enomoto‐Iwamoto, Motomi ; Mauck, Robert L. ; et al ( July 2020 , Arthritis & Rheumatology)

   To elucidate the role of decorin, a small leucine‐rich proteoglycan, in the degradation of cartilage matrix during the progression of post‐traumatic osteoarthritis (OA).

   Three‐month–old decorin‐null (Dcn^−/−) and inducible decorin‐knockout (Dcn^iKO) mice were subjected to surgical destabilization of the medial meniscus (DMM) to induce post‐traumaticOA. TheOAphenotype that resulted was evaluated by assessing joint morphology and sulfated glycosaminoglycan (sGAG) staining via histological analysis (n = 6 mice per group), surface collagen fibril nanostructure via scanning electron microscopy (n = 4 mice per group), tissue modulus via atomic force microscopy–nanoindentation (n = 5 or more mice per group) and subchondral bone structure via micro–computed tomography (n = 5 mice per group). Femoral head cartilage explants from wild‐type and Dcn^−/−mice were stimulated with the inflammatory cytokine interleukin‐1β (IL‐1β) in vitro (n = 6 mice per group). The resulting chondrocyte response toIL‐1β and release ofsGAGs were quantified.

   In both Dcn^−/−and Dcn^iKOmice, the absence of decorin resulted in acceleratedsGAGloss and formation of highly aligned collagen fibrils on the cartilage surface relative to the control (P< 0.05). Also, Dcn^−/−mice developed more salient osteophytes, illustrating more severeOA. In cartilage explants treated withIL‐1β, loss of decorin did not alter the expression of either anabolic or catabolic genes. However, a greater proportion ofsGAGs was released to the media from Dcn^−/−mouse explants, in both live and devitalized conditions (P< 0.05).

   In post‐traumaticOA, decorin delays the loss of fragmented aggrecan and fibrillation of cartilage surface, and thus, plays a protective role in ameliorating cartilage degeneration.

    

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3. Modulation of TRPV4 protects against degeneration induced by sustained loading and promotes matrix synthesis in the intervertebral disc

   https://doi.org/10.1096/fj.202201388R  

   Easson, Garrett W. D. ; Savadipour, Alireza ; Anandarajah, Akila ; Iannucci, Leanne E. ; Lake, Spencer P. ; Guilak, Farshid ; Tang, Simon Y. ( December 2022 , The FASEB Journal)

   While it is well known that mechanical signals can either promote or disrupt intervertebral disc (IVD) homeostasis, the molecular mechanisms for transducing mechanical stimuli are not fully understood. The transient receptor potential vanilloid 4 (TRPV4) ion channel activated in isolated IVD cells initiates extracellular matrix (ECM) gene expression, while TRPV4 ablation reduces cytokine production in response to circumferential stretching. However, the role of TRPV4 on ECM maintenance during tissue‐level mechanical loading remains unknown. Using an organ culture model, we modulated TRPV4 function over both short‐ (hours) and long‐term (days) and evaluated the IVDs' response. Activating TRPV4 with the agonist GSK101 resulted in a Ca²⁺flux propagating across the cells within the IVD. Nuclear factor (NF)‐κB signaling in the IVD peaked at 6 h following TRPV4 activation that subsequently resulted in higher interleukin (IL)‐6 production at 7 days. These cellular responses were concomitant with the accumulation of glycosaminoglycans and increased hydration in the nucleus pulposus that culminated in higher stiffness of the IVD. Sustained compressive loading of the IVD resulted in elevated NF‐κB activity, IL‐6 and vascular endothelial growth factor A (VEGFA) production, and degenerative changes to the ECM. TRPV4 inhibition using GSK205 during loading mitigated the changes in inflammatory cytokines, protected against IVD degeneration, but could not prevent ECM disorganization due to mechanical damage in the annulus fibrosus. These results indicate TRPV4 plays an important role in both short‐ and long‐term adaptations of the IVD to mechanical loading. The modulation of TRPV4 may be a possible therapeutic for preventing load‐induced IVD degeneration.

    

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4. Surfactant proteins and innate immunity of otitis media

   https://doi.org/10.1177/17534259221123309  

   Abdel-Razek, Osama ; Audlin, Jason ; Poe, Dennis S. ; Wang, Guirong ( October 2022 , Innate Immunity)

   Otitis media (OM) is the most common disease among young children and one of the most frequent reasons to visit the pediatrician. Development of OM requires nasopharyngeal colonization by a pathogen which must gain access to the tympanic cavity through the eustachian tube (ET) along with being able to overcome the defense mechanisms of the immune system and middle ear mucosa. OM can be caused by viral or bacterial infection. The three main bacterial pathogens are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis. Innate immunity is important in OM resolution as the disease occurs in very young children before the development of specific immunity. Elements of innate immunity include natural barriers and pattern recognition receptors such as Toll like receptors (TLRs), and Nod like receptors (NLRs). Surfactant proteins A (SP-A) and D (SP-D) act as pattern recognition receptors and are found in the lung and many other tissues including the ET and the middle ear where they probably function in host defense. Surfactant has a potential for use in the treatment of OM due to surface tension lowering function in the ET, and the possible immune functions of SP-D and SP-A in the middle ear and ET. 

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5. The Enhancer-Binding Protein MifR, an Essential Regulator of α-Ketoglutarate Transport, Is Required for Full Virulence of Pseudomonas aeruginosa PAO1 in a Mouse Model of Pneumonia

   https://doi.org/10.1128/iai.00136-22  

   Xiong, Weichuan ; Perna, Alexander ; Jacob, Ikechukwu B. ; Lundgren, Benjamin R. ; Wang, Guirong ( October 2022 , Infection and Immunity)

   Brodsky, Igor E. (Ed.)

   ABSTRACT The opportunistic human pathogen Pseudomonas aeruginosa PAO1 has an extensive metabolism, enabling it to utilize a wide range of structurally diverse compounds to meet its nutritional and energy needs. Interestingly, the utilization of some of the more unusual compounds often associated with a eukaryotic-host environment is regulated via enhancer-binding proteins (EBPs) in P. aeruginosa . Whether the utilization of such compounds and the EBPs involved contribute to the pathogenesis of P. aeruginosa remains to be fully understood. To narrow this gap, we investigated the roles of the EBPs EatR (regulator of ethanolamine catabolism), DdaR (regulator of methylarginine catabolism), and MifR (regulator of α-ketoglutarate or α-KG transport) in the virulence of P. aeruginosa PAO1 in a pneumonia-induced septic mouse model. Deletion of genes encoding EatR and DdaR had no significant effect on the mortality of P. aeruginosa PAO1-infected mice compared to wide-type (WT) PAO1-infected mice. In contrast, infected mice with Δ mifR mutant exhibited a significant reduction (~50%) in the mortality rate compared with WT PAO1 ( P < 0.05). Infected mice with Δ mifR PAO1 had lower lung injury scores, fewer inflammatory cells, decreased proinflammatory cytokines, and decreased apoptosis and cell death compared to mice infected with WT PAO1 ( P < 0.05). Furthermore, molecular analysis revealed decreased NLRP3 inflammasome activation in infected mice with Δ mifR PAO1 compared to WT PAO1 ( P < 0.05). These results suggested that the utilization of α-KG was a contributing factor in P. aeruginosa -mediated pneumonia and sepsis and that MifR-associated regulation may be a potential therapeutic target for P. aeruginosa infectious disease. 

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