Ijms 23 14883
Ijms 23 14883
Ijms 23 14883
Molecular Sciences
Review
Roles of Resolvins in Chronic Inflammatory Response
Chang Liu 1,2 , Dancai Fan 3 , Qian Lei 1,3 , Aiping Lu 1,4,5, * and Xiaojuan He 3, *
1 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases,
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
2 National TCM Key Laboratory of Serum Pharmacochemistry, Laboratory of Metabolomics, Department of
Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China
3 Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences,
Beijing 100700, China
4 Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Institute of Arthritis
Research, Shanghai Academy of Chinese Medical Sciences, Shanghai 200052, China
5 Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research,
Guangzhou 510120, China
* Correspondence: aipinglu@hkbu.edu.hk (A.L.); hxj19@126.com (X.H.)
peak period of inflammation and resolvins also promote an inflammation resolution better
than its lipid precursors at concentrations as low as one which is nanomolar [11,12].
Resolvins such as the E series from eicosapentaenoic acid (EPA), D series from docosa-
hexaenoic acid (DHA), and T series from docosapentaenoic acid (DPA) are synthesized
from essential omega-3 fatty acids by corresponding enzymes such as epoxidase and lipoxi-
dase [13,14]. Omega-3 fatty acid has been proved to be effective in treating COVID-19 [15],
cardiovascular diseases [16], cognitive impairment [17], rheumatoid arthritis [18], and
other complex diseases through an immune regulation. The actions of resolvins in the
inflammatory response mainly include reducing the PMN inflammatory infiltration [19–22],
decreasing inflammatory factors [23–28], improving inflammatory pain and preventing
a central sensitization [29]. The basic characteristics and biological effects of common
resolvins have been demonstrated. Since earlier studies were conducted on individual
subtypes of resolvins, using a different experimental design, a comparison of the results
is possible. Therefore, this paper reviews the possible effect of resolvins on promoting
an inflammation resolution under chronic inflammatory response state and explores their
clinical use to resolve inflammation.
Figure 1. The generation of D series resolvins, E series resolvins, and T series resolvins.
The T series of resolvins are derived from DPA via endothelial cyclooxygenase-2 (COX-
2). The first precursor during the production of T series resolvins is 13(R)-hydroperoxy-
docosapentaenoic acid and it is converted to 13(R)-hydroxy-docosapentaenoic acid after a
reduction [51]. When converted to 7-hydroperoxy-13(R)-hydroxy-docosapentaenoic acid,
RvT4 is obtained from the reduction in the hydroperoxy group after the transcellular
trafficking to the neutrophils [52]. The enzymatic lipoxygenase reaction occurs during
the transition to RvT1, and an allylic epoxide intermediate is formed in the process of
the conversion to RvT2 and RvT3 [53]. T series resolvins are either generated in healthy
subjects or are converted from DPA after statin therapy [4,54]. The complete stereochemical
structure of resolvins is shown in Table 1.
Int. J. Mol. Sci. 2022, 23, 14883 4 of 16
3. Resolvins Receptors
RvD1, 17R-RvD1, RvD3, 17R-RvD3, RvD5, RvE1, and 18S-RvE1 can combine with the
G protein-coupled receptor (GPR32) expressed in monocyte-macrophages, lymphocytes,
endothelial cells, and vascular smooth muscle cells, while GPR18/DRV2 is a novel discov-
ered receptor of RvD2 expressed in macrophages, neutrophils, and monocytes [55,56]. In
addition, RvD1, 17R-RvD1, and RvD3 can also combine with the G protein-coupled formyl
peptide receptor 2 (ALX/FPR2) to produce anti-inflammatory effects [57–59]. Leukotriene
B4 receptor 1 (BLT1) expressed in lymphocytes and leukocytes and ChemR23 expressed
in NK cells, macrophages, epithelial cells, and dendritic cells have been proven to be the
receptors of RvE1, 18S-RvE1, and RvE2 through target screening [60,61]. The actions of
RvD4 in the phagocytosis of human leukocytes have been suggested to be related to Gs
protein and the responding G protein-coupled receptors [39]. The resolvin receptors are cell
specific and organ specific and have been shown to be affected by disease and homeostatic
states. However, the corresponding receptors of the characterized RvD6, RvE3, and T series
of resolvins have not yet been identified, and relevant studies are still needed to explore
these receptors [62].
between epithelial and endothelial cells [63,64]. RvD1 stops neutrophil chemotaxis, inhibits
a neutrophil migration, and downregulates the actin aggregation and the expression of
adhesion molecules via miR-21 and miR-155 [65]. 17R-RvD1 decreases the expression of
p-selection and its ligand CD24 in neutrophils, while RvD2 decreases CD62L shedding in
human neutrophils [66]. Bacterial and viral infections trigger an uncontrolled inflammation
upon contact with excess NETs and clearance obstacles of NETs. The newly found T series
resolvins dose- and time-dependently reduce NETs in human neutrophils and restricted
neutrophil infiltration and NETs in a murine Staphylococcus aureus infection [67].
and downregulating the neuronal plasticity [90]. It can not only decrease the release of
TNF in LPS and IFN-γ-stimulated astrocytes, but also reduce the TNF-induced activation
of ERK1/2 [91]. Zhang et al. showed that GPR18 was expressed in astrocytes, and the acti-
vation of RvD2-GPR18 mediated an anti-nociceptive effect by regulating the Akt/GSK-3β
signal pathway in a radicular pain rat model [92].
reduces cellular infiltration, and reduces cardiac hypertrophy and fibrosis in the early
chronic phase of the disease, providing a strategy for improving drug therapy [121].
RvE1 inhibits bone resorption and osteoclastogenesis through suppressing the expression
of the transcription factors nuclear factor of activated T cells c1 (NFATc1) and c-fos [140].
6. Further Perspectives
Resolvins are a series of endogenous lipid mediators with a positive effect on inflam-
mation resolution, and their origin and chemical structure have been confirmed for many
years. Studies of receptors have reported a few receptors for resolvins; however, the recep-
tors of the T-series resolvins RvD6 and RvE3 are not clear, so a further study of resolvin
receptors can provide new evidence and directions for us to resolve inflammation. Many
human and animal experiments have also substantiated that resolvins can reduce the joint
pain and stiffness of RA, reduce vessel inflammation in coronary heart disease, promote
plaque stability, and improve the metabolic parameters and complications of diabetes.
The mechanism of action of the resolvins in the process of an inflammation resolution is
complex, and the existing evidence is only the tip of the iceberg. A large number of studies
still need to be confirmed and explained.
In inflammatory diseases, there are naturally expressed resolvins in many organs.
However, as its biosynthetic precursor omega-3 polyunsaturated fatty acid cannot be
synthesized by the human body itself, the resolvins obtained from the body are very limited.
As resolvins are endogenous lipid mediators and are sensitive to light, heat, and oxidation,
synthesis costs are very high in vitro and production supplies are limited, so it is difficult
to perform a large-scale production and new drug industry chain formation. According
to systems’ biology theory and methods, resolvins can be regarded as the breakthrough
point in the search for related correlative proteins and signaling pathways to elucidate the
mechanism of anti-inflammatory prescriptions and drugs. The cross-analysis of multiple
layers and multi-omics may be a way to provide a basis for new anti-inflammatory drugs
research to discover novel drugs with fewer side effects and significant therapeutic effects
on chronic inflammatory diseases as soon as possible.
7. Conclusions
With the development of detection techniques and a deeper understanding of the
chronic inflammatory response, the study of resolvins will no longer be limited to simple
individual subtypes of resolvins. Hence, this paper reviews not only the production process
and characteristics of resolvins but also possible mechanisms by the subtypes of resolvins
in a chronic inflammatory response and explores their clinical use to resolve inflammation.
Author Contributions: C.L. wrote the manuscript. D.F. and Q.L. participated in the writing. A.L.
and X.H. conceptualized the idea and revised the manuscript. All authors have read and agreed to
the published version of the manuscript.
Int. J. Mol. Sci. 2022, 23, 14883 11 of 16
Funding: This paper is supported by National Science Foundation of China (No. 81873053), the
Fundamental Research Funds for the Central Public Welfare Research Institutes (No. Z0736), and the
2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-
Hong Kong-Macau Joint Lab, No: 2020B1212030006).
Conflicts of Interest: The authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential conflict of interest.
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