Human neutrophil elastase inhibitors in innate and adaptive immunity

Recent evidence shows that human neutrophil elastase inhibitors can be synthesized locally at mucosal sites. In addition to efficiently targeting bacterial and host enzymes, they can be released in the interstitium and in the lumen of mucosa, where they have been shown to have antimicrobial activities, and to activate innate immune responses. This review will address more particularly the pleiotropic functions of low-molecular-mass neutrophil elastase inhibitors [SLPI (secretory leucocyte proteinase inhibitor) and elafin] and, more specifically, their role in the development of the adaptive immune response.

Download Full-text

Manipulation of Innate and Adaptive Immunity through Cancer Vaccines

Journal of Immunology Research ◽

10.1155/2017/3145742 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Elias J. Sayour ◽

Duane A. Mitchell

Keyword(s):

Immune Response ◽

Adaptive Immunity ◽

Cancer Vaccines ◽

Specific Antigen ◽

Adaptive Immune Response ◽

Innate Immune Responses ◽

Innate And Adaptive Immunity ◽

Adaptive Immune ◽

Therapeutic Setting ◽

Preclinical And Clinical Studies

Although cancer immunotherapy has shown significant promise in mediating efficacious responses, it remains encumbered by tumor heterogeneity, loss of tumor-specific antigen targets, and the regulatory milieu both regionally and systemically. Cross talk between the innate and adaptive immune response may be requisite to polarize sustained antigen specific immunity. Cancer vaccines can serve as an essential fulcrum in initiating innate immunity while molding and sustaining adaptive immunity. Although peptide vaccines have shown tepid responses in a therapeutic setting with poor correlates for immune activity, RNA vaccines activate innate immune responses and have shown promising effects in preclinical and clinical studies based on enhanced DC migration. While the mechanistic insights behind the interplay between innate and adaptive immunity may be unique to the immunotherapeutic being investigated, understanding this dynamic is important to coordinate the different arms of the immune response in a focused response against cancer antigens.

Download Full-text

Proteolytic cleavage of HLA class II by human neutrophil elastase in pneumococcal pneumonia

Scientific Reports ◽

10.1038/s41598-021-82212-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hisanori Domon ◽

Tomoki Maekawa ◽

Toshihito Isono ◽

Kazuyuki Furuta ◽

Chikara Kaito ◽

...

Keyword(s):

Immune Responses ◽

T Cell Activation ◽

Neutrophil Elastase ◽

Class Ii ◽

Proteolytic Cleavage ◽

Hla Class Ii ◽

Innate Immune ◽

Human Neutrophil Elastase ◽

Innate Immune Responses ◽

Elastase Inhibitor

AbstractBacterial and viral respiratory infections can initiate acute lung injury and acute respiratory distress syndrome. Neutrophils and their granule enzymes, including neutrophil elastase, are key mediators of the pathophysiology of acute respiratory failure. Although intracellular neutrophil elastase functions as a host defensive factor against pathogens, its leakage into airway spaces induces degradation of host connective tissue components. This leakage disrupts host innate immune responses via proteolytic cleavage of Toll-like receptors and cytokines. Here, we investigated whether neutrophils possess proteases that cleave adaptive immune molecules. We found that expression of the human leukocyte antigen (HLA) class II molecule HLA-DP β1 was decreased in THP-1-derived macrophages treated with supernatants from dead neutrophils. This decreased HLA-DP β1 expression was counteracted by treatment with neutrophil elastase inhibitor, suggesting proteolytic cleavage of HLA-DP β1 by neutrophil elastase. SDS-PAGE showed that neutrophil elastase cleaved recombinant HLA-DP α1, -DP β1, -DQ α1, -DQ β1, -DR α, and -DR β1. Neutrophil elastase also cleaved HLA-DP β1 on extracellular vesicles isolated from macrophages without triggering morphological changes. Thus, leakage of neutrophil elastase may disrupt innate immune responses, antigen presentation, and T cell activation. Additionally, inhibition of neutrophil elastase is a potential therapeutic option for treating bacterial and viral pneumonia.

Download Full-text

Toll-like receptors and diabetes: a therapeutic perspective

Clinical Science ◽

10.1042/cs20110357 ◽

2011 ◽

Vol 122 (5) ◽

pp. 203-214 ◽

Cited By ~ 63

Author(s):

Mohan R. Dasu ◽

Sandra Ramirez ◽

Roslyn R. Isseroff

Keyword(s):

Immune Responses ◽

Inflammatory Responses ◽

Adaptive Immune Response ◽

Innate Immune ◽

Undiagnosed Diabetes ◽

Innate Immune Responses ◽

Toll Like Receptors ◽

Adaptive Immune ◽

Molecular Patterns ◽

Therapeutic Perspective

Diabetes is a mutifactorial metabolic disorder that leads to a number of complications. Diabetes is estimated to affect 36 million people in the U.S.A., and the prevalence of diagnosed and undiagnosed diabetes is at 9.3% and continues to rise. Evidence from experimental animal models as well as humans has indicated that systemic inflammation plays a role in the pathophysiological processes of diabetes and is facilitated by innate immune responses. TLRs (Toll-like receptors) are key innate immune receptors that recognize conserved PAMPs (pathogen-associated molecular patterns), induce inflammatory responses essential for host defences and initiate an adaptive immune response. Although TLR expression is increased in a plethora of inflammatory disorders, the effects of metabolic aberrations on TLRs and their role in diabetes and its complications is still emerging. In the present paper, we provide a systematic review on how TLRs play a detrimental role in the pathogenic processes [increased blood sugar, NEFAs (non-esterified ‘free’ fatty acids), cytokines and ROS (reactive oxygen species)] that manifest diabetes. Furthermore, we will highlight some of the therapeutic strategies targeted at decreasing TLRs to abrogate inflammation in diabetes that may eventually result in decreased complications.

Download Full-text