Review
Abstract
Inflammasomes are high-molecular-weight cytosolic complexes that mediate the activation of caspases. There are many inflammasomes, and each is influenced by a unique pattern-recognition receptor response. Two signals are typically involved in the inflammasome pathways. Signal one involves recognition of pathogen-associated molecular patterns (PAMPs), such as LPS or other colonizing/invading microbes, that interact with TLRs, which induce the downstream production of pro–IL-1β. This is followed by signal two, which involves recognition of PAMPs or damage-associated molecular patterns (DAMPs), such as uric acid or ATP, via NLRP3, which leads to caspase-1–dependent cleavage of pro–IL-1β to active IL-1β and pyroptosis. Ultimately, these two signals cause the release of multiple proinflammatory cytokines. Both PAMPs and DAMPs can be liberated by early insults to the allograft, including ischemia/reperfusion injury, infections, and rejection. The consequence of inflammasome activation and IL-1 expression is the upregulation of adhesion molecules and chemokines, which leads to allograft neutrophil sequestration, mononuclear phagocyte recruitment, and T cell activation, all of which are key steps in the continuum from allograft insult to chronic allograft dysfunction.
Authors
S. Samuel Weigt, Vyacheslav Palchevskiy, John A. Belperio
Abstract
There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of inflammatory cytokines on osteoclast formation and function was among the most important discoveries advancing the treatment of focal osteolysis, leading to development of therapeutic agents that either directly block the bone-resorptive cell or do so indirectly via cytokine arrest. Despite these advances, a substantial number of patients with inflammatory arthritis remain resistant to current therapies, and even effective anti-inflammatory drugs frequently do not repair damaged bone. Thus, insights into events such as those impacted by inflammasomes, which signal through cytokine-dependent and -independent mechanisms, are needed to optimize treatment of inflammatory osteolysis.
Authors
Gabriel Mbalaviele, Deborah V. Novack, Georg Schett, Steven L. Teitelbaum
Abstract
Endogenous danger signals, or damage-associated molecular patterns (DAMPs), are generated in response to cell stress and activate innate immunity to provide a pivotal mechanism by which an organism can respond to damaged self. Accumulating experimental and clinical data have established the importance of DAMPs, which signal through innate pattern recognition receptors (PRRs) or DAMP-specific receptors, in regulating the alloresponse to solid organ transplantation (SOT). Moreover, DAMPs may incite distinct downstream cellular responses that could specifically contribute to the development of allograft fibrosis and chronic graft dysfunction. A growing understanding of the role of DAMPs in directing the immune response to transplantation has suggested novel avenues for the treatment or prevention of allograft rejection that complement contemporary immunosuppression and could lead to improved outcomes for solid organ recipients.
Authors
Jamie L. Todd, Scott M. Palmer
Abstract
An increasing number of older people receive organ transplants for various end-stage conditions. Although organ transplantation is an effective therapy for older patients (i.e., older than 65 years of age), such as in end-stage renal disease, this therapy has not been optimized for older patients because of our lack of understanding of the effect of aging and the immune response to organ transplantation. Here, we provide an overview of the impact of aging on both the allograft and the recipient and its effect on the immune response to organ transplantation. We describe what has been determined to date, discuss existing gaps in our knowledge, and make suggestions on necessary future studies to optimize organ transplantation for older people.
Authors
Monica M. Colvin, Candice A. Smith, Stefan G. Tullius, Daniel R. Goldstein
Abstract
Although gene-environment interactions have been investigated for many years to understand people’s susceptibility to autoimmune diseases or cancer, a role for environmental factors in modulating alloimmune responses and transplant outcomes is only now beginning to emerge. New data suggest that diet, hyperlipidemia, pollutants, commensal microbes, and pathogenic infections can all affect T cell activation, differentiation, and the kinetics of graft rejection. These observations reveal opportunities for novel therapeutic interventions to improve graft outcomes as well as for noninvasive biomarker discovery to predict or diagnose graft deterioration before it becomes irreversible. In this Review, we will focus on the impact of these environmental factors on immune function and, when known, on alloimmune function, as well as on transplant fate.
Authors
Leonardo V. Riella, Jessamyn Bagley, John Iacomini, Maria-Luisa Alegre
Abstract
Despite the prevalence of viral infections in the American population, we still have a limited understanding of how they affect pregnancy and fetal development. Viruses can gain access to the decidua and placenta by ascending from the lower reproductive tract or via hematogenous transmission. Viral tropism for the decidua and placenta is then dependent on viral entry receptor expression in these tissues as well as on the maternal immune response to the virus. These factors vary by cell type and gestational age and can be affected by changes to the in utero environment and maternal immunity. Some viruses can directly infect the fetus at specific times during gestation, while some only infect the placenta. Both scenarios can result in severe birth defects or pregnancy loss. Systemic maternal viral infections can also affect the pregnancy, and these can be especially dangerous, because pregnant women suffer higher virus-associated morbidity and mortality than do nonpregnant counterparts. In this Review, we discuss the potential contributions of maternal, placental, and fetal viral infection to pregnancy outcome, fetal development, and maternal well-being.
Authors
Karen Racicot, Gil Mor
Abstract
The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration.
Authors
Nikolaos G. Frangogiannis
Abstract
Peroxisome proliferator–activated receptors (PPARs) regulate energy metabolism and hence are therapeutic targets in metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. While they share anti-inflammatory activities, the PPAR isotypes distinguish themselves by differential actions on lipid and glucose homeostasis. In this Review we discuss the complementary and distinct metabolic effects of the PPAR isotypes together with the underlying cellular and molecular mechanisms, as well as the synthetic PPAR ligands that are used in the clinic or under development. We highlight the potential of new PPAR ligands with improved efficacy and safety profiles in the treatment of complex metabolic disorders.
Authors
Vanessa Dubois, Jérôme Eeckhoute, Philippe Lefebvre, Bart Staels
Abstract
Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with “monogenic” conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.
Authors
John C. Achermann, John Schwabe, Louise Fairall, Krishna Chatterjee
Abstract
Steroid hormones mediate critical lineage-specific developmental and physiologic responses. They function by binding their cognate receptors, which are transcription factors that drive specific gene expression programs. The requirement of most prostate cancers for androgen and most breast cancers for estrogen has led to the development of endocrine therapies that block the action of these hormones in these tumors. While initial endocrine interventions are successful, resistance to therapy often arises. We will review how steroid receptor–dependent genomic signaling is affected by genetic alterations in endocrine therapy resistance. The detailed understanding of these interactions will not only provide improved treatment options to overcome resistance, but, in the future, will also be the basis for implementing precision cancer medicine approaches.
Authors
Anna C. Groner, Myles Brown
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