The intracellular ROS accumulation in elicitor-induced immunity requires the multiple organelle-targeted Arabidopsis NPK1-related protein kinases.

Recognition at the plasma membrane of danger signals (elicitors) belonging to the classes of the microbe/pathogen- and damage-associated molecular patterns is a key event in pathogen sensing by plants and is associated with a rapid activation of immune responses. Different cellular compartments, including plasma membrane, chloroplasts, nuclei and mitochondria, are involved in the immune cellular program. However, how pathogen sensing is transmitted throughout the cell remains largely to be uncovered. Arabidopsis NPK1-related Proteins (ANPs) are mitogen-activated protein kinase kinase kinases previously shown to have a role in immunity. In this article, we studied the in vivo intracellular dynamics of ANP1- and ANP3-GFP fusions and found that under basal physiological conditions both proteins are present in the cytosol, while ANP3 is also localized in mitochondria. After elicitor perception, both proteins are present also in the plastids and nuclei, revealing a localization pattern that is so far unique. The N-terminal region of the protein kinases is responsible for their localization in mitochondria and plastids. Moreover, we found that the localization of ANPs coincides with the sites of elicitor-induced ROS accumulation and that plants lacking ANP function do not accumulate intracellular ROS.

Immune recognition of irradiated cancer cells.

Ionizing irradiation has been extensively employed for the clinical management of solid tumors, with therapeutic or palliative intents, for decades. Until recently, radiation therapy (RT) was believed to mediate antineoplastic activity mostly (if not only) as a consequence of cancer cell-intrinsic effects. Indeed, the macromolecular damage imposed to malignant cells by RT initiates one or multiple signal transduction cascades that drive a permanent proliferative arrest (cellular senescence) or regulated cell death. Both these phenomena show a rather linear dose-response correlation. However, RT also mediates consistent immunological activity, not only as an "on-target effect" originating within irradiated cancer cells, but also as an "off-target effect" depending on the interaction between RT and stromal, endothelial, and immune components of the tumor microenvironment. Interestingly, the immunological activity of RT does not exhibit linear dose-response correlation. Here, we discuss the mechanisms whereby RT alters the capacity of the immune system to recognize and eliminate irradiated cancer cells, either as an "on-target" or as on "off-target" effect. In particular, we discuss the antagonism between the immunostimulatory and immunosuppressive effects of RT as we delineate combinatorial strategies to boost the former at the expenses of the latter.

Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses.

The immunogenicity of cancer cells is an emerging determinant of anti-cancer immunotherapy. Beyond developing immunostimulatory regimens like dendritic cell-based vaccines, immune-checkpoint blockers, and adoptive T-cell transfer, investigators are beginning to focus on the immunobiology of dying cancer cells and its relevance for the success of anticancer immunotherapies. It is currently accepted that cancer cells may die in response to anti-cancer therapies through regulated cell death programs, which may either repress or increase their immunogenic potential. In particular, the induction of immunogenic cancer cell death (ICD), which is hallmarked by the emission of damage-associated molecular patterns (DAMPs); molecules analogous to pathogen-associated molecular patterns (PAMPs) acting as danger signals/alarmins, is of great relevance in cancer therapy. These ICD-associated danger signals favor immunomodulatory responses that lead to tumor-associated antigens (TAAs)-directed T-cell immunity, which paves way for the removal of residual, treatment-resistant cancer cells. It is also emerging that cancer cells succumbing to ICD can orchestrate "altered-self mimicry" i.e. mimicry of pathogen defense responses, on the levels of nucleic acids and/or chemokines (resulting in type I interferon/IFN responses or pathogen response-like neutrophil activity). In this review, we exhaustively describe the main molecular, immunological, preclinical, and clinical aspects of immunosuppressive cell death or ICD (with respect to apoptosis, necrosis and necroptosis). We also provide an extensive historical background of these fields, with special attention to the self/non-self and danger models, which have shaped the field of cell death immunology.

Key Elements of Gingival Epithelial Homeostasis upon Bacterial Interaction.

Epithelia are structurally integral elements in the fabric of oral mucosa with significant functional roles. Similarly, the gingival epithelium performs uniquely critical tasks in responding to a variety of external stimuli and dangers through the regulation of specific built-in molecular mechanisms in a context-dependent fashion at cellular levels. Gingival epithelial cells form an anatomic architecture that confers defense, robustness, and adaptation toward external aggressions, most critically to colonizing microorganisms, among other functions. Accordingly, recent studies unraveled previously uncharacterized response mechanisms in gingival epithelial cells that are constructed to rapidly exert biocidal effects against invader pathobiotic bacteria, such as Porphyromonas gingivalis, through small danger molecule signaling. The host-adapted bacteria, however, have developed adroit strategies to 1) exploit the epithelia as privileged growth niches and 2) chronically target cellular bactericidal and homeostatic metabolic pathways for successful bacterial persistence. As the overgrowth of colonizing microorganisms in the gingival mucosa can shift from homeostasis to dysbiosis or a diseased state, it is crucial to understand how the innate modulatory molecules are intricately involved in antibacterial pathways and how they shape susceptibility versus resistance in the epithelium toward pathogens. Thus, in this review, we highlight recent discoveries in gingival epithelial cell research in the context of bacterial colonizers. The current knowledge outlined here demonstrates the ability of epithelial cells to possess highly organized defense machineries, which can jointly regulate host-derived danger molecule signaling and integrate specific global responses against opportunistic bacteria to combat microbial incursion and maintain host homeostatic balance. These novel examples collectively suggest that the oral epithelia are equipped with a dynamically robust and interconnected defense system encompassing sensors and various effector molecules that arrange and achieve a fine-tuned and advanced response to diverse bacteria.

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications.

Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. Both resiquimod and motolimod operate as agonists of Toll-like receptor 7 (TLR7) and/or TLR8, in thus far delivering adjuvant-like signals to antigen-presenting cells (APCs). In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines. Here, we summarize preclinical and clinical evidence recently collected to support the development of resiquimod and motolimod and other TLR7/TLR8 agonists as anticancer agents.

Secondary Necrosis: Accidental No More.

Recent data demonstrate that secondary necrosis is not an accidental epiphenomenon of apoptosis, but a finely regulated process with prominent pathophysiological and therapeutic implications. The molecular machinery that controls secondary necrosis stands out as a promising target for the development of novel drugs that may increase the immunogenicity of cancer cells succumbing to treatment.

Prelude to oral microbes and chronic diseases: past, present and future.

Associations between oral and systemic health are ancient. Oral opportunistic bacteria, particularly, Porphyromonas gingivalis and Fusobacterium nucleatum, have recently been deviated from their traditional roles as periodontal pathogens and arguably ascended to central players based on their participations in complex co-dependent mechanisms of diverse systemic chronic diseases risk and pathogenesis, including cancers, rheumatoid-arthritis, and diabetes.

Role of Apoptosis in Amplifying Inflammatory Responses in Lung Diseases.

Apoptosis is an important contributor to the pathophysiology of lung diseases such as acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD). Furthermore, the cellular environment of these acute and chronic lung diseases favors the delayed clearance of apoptotic cells. This dysfunctional efferocytosis predisposes to the release of endogenous ligands from dying cells. These so-called damage-associated molecular patterns (DAMPs) play an important role in the stimulation of innate immunity as well as in the induction of adaptive immunity, potentially against autoantigens. In this review, we explore the role of apoptosis in ALI and COPD, with particular attention to the contribution of DAMP release in augmenting the inflammatory response in these disease states.