Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases

Airborne pathogens and environmental stimuli evoke immune responses in the lung. It is critical to health that these responses be controlled to prevent tissue damage and the compromise of organ function. Resolution of inflammation is a dynamic process that is coordinated by biochemical and cellular mechanisms. Recently, specialized proresolving mediators (SPMs) have been identified in resolution exudates. These molecules orchestrate anti-inflammatory and proresolving actions that are cell type specific. In this review, we highlight SPM biosynthesis, the influence of SPMs on the innate and adaptive immune responses in the lung, as well as recent insights from SPMs on inflammatory disease pathophysiology. Uncovering these mediators and cellular mechanisms for resolution is providing new windows into physiology and disease pathogenesis.

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Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5

Journal of Experimental Medicine ◽

10.1084/jem.20180314 ◽

2018 ◽

Vol 215 (11) ◽

pp. 2901-2918 ◽

Cited By ~ 13

Author(s):

Maria Buxadé ◽

Hector Huerga Encabo ◽

Marta Riera-Borrull ◽

Lucía Quintana-Gallardo ◽

Pilar López-Cotarelo ◽

...

Keyword(s):

Transcription Factor ◽

Immune Responses ◽

T Lymphocyte ◽

Cell Type ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Cell Type Specific ◽

Antigen Presenting ◽

Mhcii Expression

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type–specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita. This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.

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Optimizing Dendritic Cell-Based Immunotherapy: Tackling the Complexity of Different Arms of the Immune System

Mediators of Inflammation ◽

10.1155/2012/690643 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 23

Author(s):

Ilse Van Brussel ◽

Zwi N. Berneman ◽

Nathalie Cools

Keyword(s):

Immune System ◽

Dendritic Cell ◽

Immune Responses ◽

Adaptive Immune System ◽

Cellular Mechanisms ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

New Ideas ◽

And Function

Earlier investigations have revealed a surprising complexity and variety in the range of interaction between cells of the innate and adaptive immune system. Our understanding of the specialized roles of dendritic cell (DC) subsets in innate and adaptive immune responses has been significantly advanced over the years. Because of their immunoregulatory capacities and because very small numbers of activated DC are highly efficient at generating immune responses against antigens, DCs have been vigorously used in clinical trials in order to elicit or amplify immune responses against cancer and chronic infectious diseases. A better insight in DC immunobiology and function has stimulated many new ideas regarding the potential ways forward to improve DC therapy in a more fundamental way. Here, we discuss the continuous search for optimal in vitro conditions in order to generate clinical-grade DC with a potent immunogenic potential. For this, we explore the molecular and cellular mechanisms underlying adequate immune responses and focus on most favourable DC culture regimens and activation stimuli in humans. We envisage that by combining each of the features outlined in the current paper into a unified strategy, DC-based vaccines may advance to a higher level of effectiveness.

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Polyelectrolyte Coating of Ferumoxytol Differentially Impacts on Labeling of Inflammatory and Steady-State Dendritic Cell Subtypes

10.1101/2021.05.27.445994 ◽

2021 ◽

Author(s):

Nehar Celikkin ◽

John E. Wong ◽

Martin Zenke ◽

Thomas Hieronymus

Keyword(s):

Steady State ◽

Immune Responses ◽

Transplant Rejection ◽

Specific Treatment ◽

Cellular Responses ◽

Cell Type ◽

Adaptive Immune ◽

Inflammatory Conditions ◽

Cell Type Specific ◽

The Impact

Engineered magnetic nanoparticles (MNPs) are emerging as advanced tools for medical applications. The coating of MNPs using polyelectrolytes (PEs) is a versatile means to tailor MNP properties and is used to optimize MNP functionality. Dendritic cells (DCs) are critical regulators of adaptive immune responses. Functional distinct DC subsets exist either under steady-state or inflammatory conditions, which are explored for the specific treatment of various diseases, such as cancer, autoimmunity or transplant rejection. Here, the impact of PE coating of ferumoxytol for uptake into both inflammatory and steady-state DCs and cellular responses to the MNP labeling is addressed. Labeling efficiency by uncoated and PE-coated ferumoxytol is highly variable in different DC subsets, and PE coating significantly improves the labeling of steady-state DCs. Uncoated ferumoxytol results in increased cytotoxicity of steady-state DCs after labeling that is abolished by the PE coating, while no increased cell death is observed in inflammatory DCs. Furthermore, uncoated and PE-coated ferumoxytol appears immunologically inert in inflammatory DCs but induces activation of steady-state DCs. These results show that PE coating of MNPs can be applied to endow particles with desired properties for enhanced uptake and cell type-specific responses in distinct target DC populations.

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Circadian clocks guide dendritic cells into skin lymphatics

Nature Immunology ◽

10.1038/s41590-021-01040-x ◽

2021 ◽

Author(s):

Stephan J. Holtkamp ◽

Louise M. Ince ◽

Coline Barnoud ◽

Madeleine T. Schmitt ◽

Flore Sinturel ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Lymphatic Vessels ◽

Migration Pattern ◽

Circadian Clocks ◽

Leukocyte Trafficking ◽

Lymphatic Endothelial Cells ◽

Cell Type ◽

Adaptive Immune Responses ◽

Adaptive Immune

AbstractMigration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.

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