Neutrophils are innate immune cells with important roles in antimicrobial defense. However, impaired or dysregulated neutrophil function can result in host tissue damage, loss of homeostasis, hyperinflammation or pathological immunosuppression. A central link between neutrophil activation and immune outcomes is emerging to be the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, which is activated by neutrophil detection of a microbial threat via pattern recognition receptors and results in inflammatory cytokine production. This potent pro-inflammatory pathway is also the target of several immunosuppressive drugs used for the treatment of autoimmune disorders, during solid organ and hematopoietic cell transplantations, and as a part of anti-cancer therapy: but what effects these drugs have on neutrophil function, and their broader consequences for immune homeostasis and microbial defense are not yet known. Here, we bring together the emerging literature describing pathology- and drug- induced neutrophil impairment, with particular focus on their effects on calcineurin-NFAT signaling in the innate immune compartment.

• Keywords
• NFAT signaling, calcineurin inbibitors, immunosuppression, neutrophil (PMN) function, pattern recognition receptor (PRR), sepsis,
• MeSH
• Cytokines immunology   metabolism   MeSH
• Homeostasis immunology   MeSH
• Immune Tolerance immunology   MeSH
• Calcineurin immunology   metabolism   MeSH
• Humans MeSH
• Inflammation Mediators immunology   metabolism   MeSH
• Neutrophils immunology   metabolism   MeSH
• Immunity, Innate immunology   MeSH
• Receptors, Pattern Recognition immunology   metabolism   MeSH
• Signal Transduction immunology   MeSH
• NFATC Transcription Factors immunology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Cytokines MeSH
• Calcineurin MeSH
• Inflammation Mediators MeSH
• Receptors, Pattern Recognition MeSH
• NFATC Transcription Factors MeSH

Mesenchymal stromal cells (MSCs) combined with calcineurin-nuclear factor of activated T cell (CN-NFAT) inhibitors are being tested as a treatment for graft-versus-host disease (GvHD). The immunosuppressive properties of MSCs seem beneficial; however, their response during fungal infection, which is an important cause of mortality in patients with GvHD , is unknown. We report that MSCs phagocytose the fungal component zymosan, resulting in phosphorylation of spleen tyrosine kinase (Syk), increase in cytosolic calcium levels, and ultimately, increase in NFAT1 nuclear translocation. RNA sequencing analysis of zymosan-treated MSCs showed that CN-NFAT inhibition affects extracellular matrix (ECM) genes but not cytokine expression that is under the control of the NF-κB pathway. When coculturing MSCs or decellularized MSC-ECM with human peripheral blood mononuclear cells (PBMCs), selective NFAT inhibition in MSCs decreased cytokine expression by PBMCs. These findings reveal a dual mechanism underlying the MSC response to zymosan: while NF-κB directly controls inflammatory cytokine expression, NFAT impacts immune-cell functions by regulating ECM remodeling.

• Keywords
• Immunology, Mycology,
• Publication type
• Journal Article MeSH

IL-2 was initially characterized as a T cell growth factor in the 1970s, and has been studied intensively ever since. Decades of research have revealed multiple and diverse roles for this potent cytokine, indicating a unique linking role between adaptive and innate arms of the immune system. Here, we review the literature showing that IL-2 is expressed in a plethora of cell types across the immune system, where it has indispensable functions in orchestrating cellular interactions and shaping the nature and magnitude of immune responses. Emerging from the basic research that has revealed the molecular mechanisms and the complexity of the biologic actions of IL-2, several immunotherapeutic approaches have now focused on manipulating the levels of this cytokine in patients. These strategies range from inhibition of IL-2 to achieve immunosuppression, to the application of IL-2 as a vaccine adjuvant and in cancer therapies. This review will systematically summarize the major findings in the field and identify key areas requiring further research in order to realize the potential of IL-2 in the treatment of human diseases.

• Keywords
• Tacrolimus, calcineurin inhibitors, cyclosporine A, monocytes, myeloid cells,
• MeSH
• Adaptive Immunity * MeSH
• Immunotherapy * MeSH
• Interleukin-2 metabolism   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Immunity, Innate * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Interleukin-2 MeSH