Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by excessive inflammatory and immune responses and tissue damage. Increasing evidence has demonstrated the important role of programmed cell death in SLE pathogenesis. When apoptosis encounters with defective clearance, accumulated apoptotic cells lead to secondary necrosis. Different forms of lytic cell death, including secondary necrosis after apoptosis, NETosis, necroptosis, and pyroptosis, contribute to the release of damage-associated molecular patterns (DAMPs) and autoantigens, resulting in triggering immunity and tissue damage in SLE. However, the role of autophagy in SLE pathogenesis is in dispute. This review briefly discusses different forms of programmed cell death pathways and lay particular emphasis on inflammatory cell death pathways such as NETosis, pyroptosis, and necroptosis and their roles in the inflammatory and immune responses in SLE.

/pdf/programmed-cell-death-pathways-in-the-pathogenesis-of-4ppt1fsvo7.pdf

Programmed Cell Death Pathways in the Pathogenesis of Systemic Lupus Erythematosus

MicroRNAs as major regulators of the autophagy pathway

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression post-transcriptionally by targeting either the 3′ untranslated or coding regions of genes. They have been reported to play key roles in a wide range of biological processes. The recent remarkable developments of transcriptomics technologies, especially next-generation sequencing technologies and advanced bioinformatics tools, allow more in-depth exploration of messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs), including miRNAs. These technologies have offered great opportunities for a deeper exploration of miRNA involvement in farm animal diseases, as well as livestock productivity and welfare. In this review, we provide an overview of the current knowledge of miRNA roles in major farm animal diseases with a particular focus on diseases of economic importance. In addition, we discuss the steps and future perspectives of using miRNAs as biomarkers and molecular therapy for livestock disease management as well as the challenges and opportunities for understanding the regulatory mechanisms of miRNAs related to disease pathogenesis.

https://www.mdpi.com/1422-0067/22/6/3080/pdf

miRNA Regulatory Functions in Farm Animal Diseases, and Biomarker Potentials for Effective Therapies

Nilotinib, a tyrosine kinase inhibitor, has been studied extensively in various tumor models; however, no information exists about the pharmacological action of nilotinib in bacterial infections. Mycobacterium bovis (M. bovis) and Mycobacterium avium subspecies paratuberculosis (MAP) are the etiological agents of bovine tuberculosis and Johne’s disease, respectively. Although M. bovis and MAP cause distinct tissue tropism, both of them infect, reside, and replicate in mononuclear phagocytic cells of the infected host. Autophagy is an innate immune defense mechanism for the control of intracellular bacteria, regulated by diverse signaling pathways. Here we demonstrated that nilotinib significantly inhibited the intracellular survival and growth of M. bovis and MAP in macrophages by modulating host immune responses. We showed that nilotinib induced autophagic degradation of intracellular mycobacterium occurred via the inhibition of PI3k/Akt/mTOR axis mediated by abelson (c-ABL) tyrosine kinase. In addition, we observed that nilotinib promoted ubiquitin accumulation around M. bovis through activation of E3 ubiquitin ligase parkin. From in-vivo experiments, we found that nilotinib effectively controlled M. bovis growth and survival through enhanced parkin activity in infected mice. Altogether, our data showed that nilotinib regulates protective innate immune responses against intracellular mycobacterium, both in-vitro and in-vivo, and can be exploited as a novel therapeutic remedy for the control of M. bovis and MAP infections.

https://www.mdpi.com/2073-4409/8/5/506/pdf

Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy.

Mitophagy is a selective autophagy mechanism for eliminating damaged mitochondria and plays a crucial role in the immune evasion of some viruses and bacteria. Here, we report that Mycobacterium bovis (M. bovis) utilizes host mitophagy to suppress host xenophagy to enhance its intracellular survival. M. bovis is the causative agent of animal tuberculosis and human tuberculosis. In the current study, we show that M. bovis induces mitophagy in macrophages, and the induction of mitophagy is impaired by PINK1 knockdown, indicating the PINK1-PRKN/Parkin pathway is involved in the mitophagy induced by M. bovis. Moreover, the survival of M. bovis in macrophages and the lung bacterial burden of mice are restricted by the inhibition of mitophagy and are enhanced by the induction of mitophagy. Confocal microscopy analysis reveals that induction of mitophagy suppresses host xenophagy by competitive utilization of p-TBK1. Overall, our results suggest that induction of mitophagy enhances M. bovis growth while inhibition of mitophagy improves growth restriction. The findings provide a new insight for understanding the intracellular survival mechanism of M. bovis in the host.

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2021.1987671

Mycobacterium bovis induces mitophagy to suppress host xenophagy for its intracellular survival.

The mechanism by which microRNAs (miRNAs) modulate innate immunity and autophagy has not been fully elucidated in Mycobacterium bovis (M. bovis) infections. In this study, we identified that miR-199a inhibited key innate immune responses and autophagy in murine macrophages infected with M. bovis. Using ex vivo and in vitro approaches we show that the expression of miR-199a was significantly increased during M. bovis infection. Furthermore, miR-199a suppressed autophagy and interferon-β (IFN-β) production by directly targeting TANK-binding kinase 1 (TBK1) mRNA in both J774a.1 and BMDM cells. Upregulation of miR-199a or TBK1 silencing (siTBK1) inhibited maturation of autophagosomes and increased M. bovis survival. Our results demonstrate that, by targeting of TBK1, miR-199a modulates innate immune responses and promote the intracellular survival and growth of M. bovis.

/pdf/microrna-199a-inhibits-cellular-autophagy-and-downregulates-3ij2ti8xkx.pdf

MicroRNA-199a Inhibits Cellular Autophagy and Downregulates IFN-β Expression by Targeting TBK1 in Mycobacterium bovis Infected Cells.

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MicroRNA-199a Inhibits Cellular Autophagy and Downregulates IFN-β Expression by Targeting TBK1 in Mycobacterium bovis Infected Cells.