cells
Editorial
Leukocytes in Inflammation, Resolution of Inflammation,
Autoimmune Diseases and Cancer
János G. Filep
Department of Pathology and Cell Biology, University of Montreal, Montreal, QC H1T 2M4, Canada;
janos.g.filep@umontreal.ca
Citation: Filep, J.G. Leukocytes in
Inflammation, Resolution of
Inflammation, Autoimmune Diseases
and Cancer. Cells 2021, 10, 1735.
https://doi.org/10.3390/cells10071735
Received: 29 June 2021
Accepted: 1 July 2021
Published: 9 July 2021
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Inflammation is a double-edged sword. Acute inflammation is broadly defined as a
protective response of the organism to invading pathogens and tissue injury. The reaction
should ideally be localized and self-limited, leading to the elimination of pathogens and
damaged cells, and the clearance of inflammatory cells, followed by tissue repair and
return to homeostasis [1,2]. Excessive inflammation or failure of the initial response to
resolve in a timely manner results in nonresolving inflammation, which is now considered
the critical component of many chronic human diseases, including atherosclerosis, arthritis,
pulmonary diseases, autoimmunity, diabetes and cancer [3]. The inflammatory response
is a complex process, heterogeneous in nature and depends on the type of disease and
organ in which it occurs. The sequence of events and signaling circuits initiated during
inflammation and the dual nature of inflammation has received considerable attention
and is summarized in guiding maps for inflammation [4] and resolution pathways [5].
However, accumulating data expand and challenge many of our current concepts. Thus,
identifying macrophage and neutrophil functional heterogeneity, the characterization of
novel mechanisms and the recognition of resolution as an active process governed by
specialized pro-resolving mediators shed new light on the roles of leukocyte subsets in
acute and chronic inflammatory conditions. Since the inflammatory response is critical for
survival, the current anti-inflammatory therapies have limitations and often do not lead
to the repair of affected tissues. A better understanding of inflammatory and resolution
pathways will likely enable further therapeutic advances. This Special Issue of Cells covers
a broad spectrum of diseases, including rheumatoid arthritis-associated cardiovascular
diseases, chronic respiratory diseases, acute-on-chronic liver failure, pregnancy-associated
hypertension and eclampsia, and autoimmune diseases, in which leukocytes play critical
pathophysiological roles. This collection of articles, both review and original research papers, highlights recent advances in elucidating leukocyte-centered mechanisms under these
pathological conditions and discuss new avenues for potential therapeutic interventions to
promote repair and return to homeostasis.
Rheumatoid arthritis is an autoimmune disease characterized by inflammation within
synovial joints and an independent risk factor for cardiovascular diseases. Chen and
colleagues [6] review the link between inflammation and non-ischemic cardiac diseases in
patients with rheumatoid arthritis, with a particular focus on heart failure with preserved
ejection fraction (HFpEF). HFpEF likely represents a distinct mechanism of heart failure, as
therapies for heart failure with reduced ejection fraction have limited success in HFpEF
patients. The authors argue that local or systemic inflammation may either directly affect
the heart or render the heart more susceptible to traditional risk factors. Indeed, rheumatoid arthritis is associated with increased circulating levels of pro-inflammatory mediators,
which promote the recruitment of leukocytes into cardiac tissue, in particular MHCIIhigh
macrophages, evoke oxidative stress, cardiac muscle hypertrophy and increased stiffness,
ultimately leading to diastolic dysfunction. While a number of biological and synthetic
disease modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs and corticosteroids can improve clinical symptoms, they have little impact on the development
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of heart failure, or some drugs could even increase the risk of non-ischemic heart failure.
As the progression of rheumatoid arthritis is now increasingly recognized as a result of
defective resolution mechanism [7], failed resolution pathways could also underlie the development of HFpEF. The authors analyze preclinical data, indicating the cardioprotective
effects of formyl-peptide receptor 2 (FPR2) agonists lipoxin A4 , resolvin D1, annexin A1
and the synthetic compound 17b (CMPD17b). Another option is the use of statins, which
are generally prescribed to lower plasma cholesterol level. However, statins have been
shown to increase the production of 15-epi-LXA4 and 13-series resolvins, thereby correcting
the inflammation resolution deficit independent of their lipid-lowering capacity.
Casulleras and colleagues [8] describe the prevailing characteristics of the hyperinflammatory state underlying the development of acute-on-chronic liver failure in patients,
which is associated with high short-term mortality. Although, at present, only limited information is available on the triggers of acute-on-chronic liver failure, inappropriate response
of both the innate and adaptive immune system (leading to altered function and metabolism
in neutrophils, monocytes, METK+ macrophages and NK cells) to pathogen-associated
molecular patterns and/or damage-associated molecular patterns drive the rapid deterioration in liver function. This response is frequently associated with an immunosuppressionlike state in patients, possibly due to the presence of a more tolerogenic phenotype of
immune cells in the liver, which is not present in circulating counterparts. In addition
to liver transplantation, the most efficient therapy for acute-on-chronic liver failure, the
authors also discuss several potential therapeutic interventions to limit the deleterious
consequences of misbalanced immune reactions. Among these options are treatment with
human serum albumin that exerts immunomodulatory actions in leukocytes by blocking
Toll-like receptor signaling pathways in the endosomal compartment [9], TLR4 antagonists,
IL-22, G-CSF and stem cell therapy.
The lung has long been recognized to have a significant reparative capacity in response
to injury. Dysregulated inflammation and aberrant or defective repair mechanisms are
increasingly being recognized as central events in several chronic pulmonary pathologies,
including chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and
acute respiratory distress syndrome (ARDS) [10]. Croasdell Lucchini and colleagues [11]
review the plasticity of respiratory epithelial cells to respond to injury and to activate
injury-specific regenerative processes through crosstalk with immune cells (particularly
granulocytes and macrophages). Epithelial crosstalk with other cell types is mediated
by altered cytokine profiles, the secretion of growth factors, and the generation of proresolving mediators, extracellular vesicles and miRNAs. Preclinical models indicate the
beneficial actions of the therapeutic targeting of soluble mediators, signaling cascades and
epithelial repair mechanisms; however, translating these approaches to the clinical setting
will require further studies.
Accumulating data indicate a role for inflammation in the development of pregnancyinduced hypertension and preeclampsia. Socha et al. [12] discuss how the activation of the
NLRP3 inflammasome by hypercholesterolemia, hyperglycemia or hyperuricemia initiates
a feed-forward loop, consisting of local inflammation, sympathetic outflow and increased
production of angiotensin II, which leads to hypertension and vascular injury. NLRP3
activation also underpins renal injury, enhanced coagulation and thrombus formation,
and placental abruption, hallmarks of preeclampsia. These findings identify the NLRP3
inflammasome as a potential therapeutic target for the prevention and/or treatment of
pregnancy-induced hypertension and preeclampsia.
Sanches and colleagues [13] report a dual role for the glucocorticoid-regulated protein annexin A1 in the regulation of the NLRP3 inflammasome in murine neutrophils.
Neutrophils are an important source of, and cellular targets for, annexin A1 [14]. The
genetic deletion of annexin A1 resulted in reduced IL-1β release and altered the lipid
profile, indicating a role for endogenous annexin A1 in the proper activation of NLRP3
machinery. By contrast, the treatment of neutrophils with annexin A1-derived peptide
Ac2-26 markedly suppressed NLRP3 activation by nigericin or ATP parallel with increases
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in the levels of phosphatidylserine and oxidized phosphocholines, known biomarkers of
the inflammation resolution circuits. Based on previous reports, the authors suggest that
peptide Ac2-26 triggers the production of anti-inflammatory microvesicles and activates
the intrinsic pro-apoptosis program in neutrophils.
Similar to T cell and macrophage subsets, accumulating evidence indicates the unexpected heterogeneity and functional versatility of neutrophil granulocytes [15]. Changes in
the neutrophil secretome, including cytokines, granular proteins, neutrophil extracellular
traps and extracellular vesicles have received considerable attention, likely because of
their importance in the inflammatory process. Kolonics and colleagues [16] provide an
overview of extracellular vesicles as intercellular communication tools in homeostasis
and under pathological conditions, including tumor progression, rheumatoid arthritis,
autoimmunity and neurodegenerative diseases. The authors detail the composition and
functional heterogeneity of neutrophil-derived extracellular vesicles, ranging from the
spontaneous release of extracellular vesicles from unstimulated cells to those released in
response to pathogens, bacterial constituents, pro-inflammatory mediators, pharmacological or environmental stimuli. In general, extracellular vesicles derived from resting and
apoptotic neutrophils tend to send anti-inflammatory signals to neighboring cells, whereas
activated neutrophils tend to release extracellular vesicles that generate pro-inflammatory
signals to facilitate host defense. Since extracellular vesicles derived from the same neutrophil population can have diverse and sometimes even opposing actions on different
target cells, depending on the cues received from the inflammatory microenvironment, the
authors propose a continuous spectrum concept, where the released extracellular vesicles
reflect the prevailing state of the parent cells. This concept may also raise the possibility
of monitoring neutrophil extracellular vesicle composition as a potential biomarker and
developing anti-inflammatory neutrophil extracellular vesicles as a therapeutic tool.
Tumor cell-derived exosomes have long been recognized to mediate cellular crosstalk
within the tumor microenvironment to drive tumor progression [17]. Making another step
forward, Pritchard and colleagues [18] report that lung adenocarcinoma cell-derived exosomes induced transcriptional changes and reprogrammed metabolism in non-committed
(M0) macrophages, resulting in their polarization to the M2 phenotype in vitro. Likewise,
the co-culture of murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) with Lewis lung carcinoma (LLC)-derived exosomes resulted in M2
macrophages. Interestingly, p53 regulated exosome production, whereas macrophage polarization occurred in a p53-independent fashion. These findings reveal a regulatory role of
tumor-derived exosomes in promoting the polarization of tumor-associated macrophages
in the lung towards the M2 phenotype, leading to immune suppression and the promotion
of tumor growth.
Alternately activated M2-like macrophages also govern the remodeling of the extracellular matrix, a characteristic feature of many chronic respiratory diseases, such as
idiopathic pulmonary fibrosis, chronic obstructive pulmonary diseases (COPD) and severe
asthma [10]. Ho and colleagues [19] report that the transient pulmonary overexpression
of oncostatin M or IL-6, members of the gp130 cytokine family, induced the expression
of resistin-like molecule alpha (RELMα or FIZZ1, found in inflammatory zone 1), independent of IL-6 or STAT6 in mouse airway epithelial cells. These mechanisms contrast
STAT6-mediated actions of oncostatin M on type 2 alveolar epithelial cells and the recruitment and polarization of macrophages towards the M2 phenotype, leading to RELMα
release and the subsequent induction of extracellular matrix modulating genes. Although
the human homolog for mouse RELMα has yet to be identified, these findings call for
further studies on the role of RELM family proteins in lung pathologies associated with
elevated oncostatin M levels.
As highlighted by these and numerous other previous studies, macrophage subsets are
attractive therapeutic targets for the treatment of a wide range of common pathologies [20].
Poltavets and colleagues [21] provide an overview of key signaling molecules from surface
markers through receptors and chemokines/cytokines to transcription factors, which
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characterize and drive M1 and M2 polarization. The authors argue that macrophages
are easily reprogrammable cells and discuss strategies of target selection, methods of
vector delivery and genome editing approaches to achieve the controllable promotion
of the desired M1 or M2 phenotype, depending on the pathological conditions. Two
rapidly developing approaches to obtain macrophages, the induced pluripotent stem
cell technologies (iPSCs) and the use of engineered transcription activator-like effector
nucleases (TALEN), hold promise for repair-facilitating interventions. Generating iPSCs
from peripheral blood monocytes is less invasive than the use of skin fibroblasts. The
feasibility of TALEN-promoted insertion codon-optimized cDNA for the generation of
functionally corrected monocytes and macrophages has recently been shown to efficiently
correct a defect in the CSF2RA gene, which results in life-threatening hereditary pulmonary
alveolar proteinosis.
Jin and colleagues [22] report that the infection of macrophages and lymphocytes
to Theiler’s murine encephalomyelitis virus (TMEV), which induces an inflammatory
demyelinating disease in susceptible mice similar to human multiple sclerosis, resulted
in viral replication and the subsequent stimulation of dendritic cells, macrophages, B
cells and T cells. TMEV-infected B cells exhibited elevated antigen-presenting function
and produced autoantibodies. TMEV-infected antigen-presenting cells released excessive
amounts of type I interferons, IL-6, IL-1 and prostaglandin E2, which contributed to a
shift from the protective Th1 response to pathogenic Th17 response. These findings may
imply a potentially important role for microbial infection in the induction or progression of
autoimmune diseases.
Moerman-Herzog and colleagues [23] provide an overview of the clinical features and
gene expression profiles aiming to distinguish benign and malignant lymphoproliferative
phenotypes, in particular Sézary syndrome, an aggressive cutaneous T cell lymphoma,
and lymphocytic-variant hypereosinophilic syndrome (L-HES). Shared features of these
two syndromes include T cell proliferation and a Th2-like phenotype. IL17RB expression
appears to be selective for L-HES, whereas Sézary syndrome is associated with the expression of a number of cancer-promoting genes, and genes associated with regulatory and
exhaustion phenotype, and EMT, including PLS3 and TWIST, the loss of STAT4 expression
and the co-expression of oncogenic microRNAs. The identification of gene subsets that are
unique to each disease will likely improve diagnostic accuracy. Functional studies with
these genes will yield further insight into the pathogenesis of Sézary syndrome.
In conclusion, the Special Issue “Leukocytes in Inflammation, Resolution of Inflammation, Autoimmune Diseases and Cancer” presents a selection of studies that elucidate the
diverse roles of leukocytes in inflammation, underlying a range of pathologies. Although
leukocytes have been and still are intensely studied, the knowledge of many aspects of
their functions, in particular those orchestrating repairs and the resolution of inflammation,
is only beginning to emerge. A deeper understanding of how this dichotomy is regulated
and to what extent these features can be exploited to promote resolution and repair in
patients represent quite exciting lines of ongoing and future investigations.
Funding: This work was supported by grants from the Canadian Institutes of Health Research
(MOP-97742 and MOP-102619).
Conflicts of Interest: The author declares no conflict of interest.
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