November 16-17, 2021
Background
Upon an environmental or biobehavioral injury, such as infection or physical trauma, a prompt inflammatory response is critical; however, acute inflammation must be temporary. If the resolution and post-resolution phases of inflammation are not well-controlled, prolonged leukocyte recruitment and infiltration may lead to excessive inflammation and maladapted homeostasis. Ultimately, dysfunctional resolution of inflammation may directly link to chronic inflammation, a common and devastating component of many diseases and conditions within the NIAMS purview.
To improve understanding of the intrinsic mechanisms of inflammation resolution and of how dysregulated resolution may lead to chronic inflammation, the NIAMS held a roundtable on emerging opportunities in research on resolution of inflammation. The meeting brought together researchers from the NIH extramural and intramural community, within and outside of the NIAMS mission areas, along with a patient representative to identify unmet needs, explore areas for potential collaboration, and discuss new ways to improve outcomes for diseases within the NIAMS mission. NIAMS staff along with colleagues from the FDA and other NIH institutes with an interest in inflammation resolution also attended the meeting. The roundtable was videocast and recordings of the first and second days of the meeting are available on the NIH videocast archive. In advance of the meeting, the Institute collected written input from the participants, who also canvassed their research communities, on the questions below.
- What knowledge has been gained from preclinical and clinical research into the cellular and molecular mediators of inflammation resolution?
- What are salient strategies to elucidate inflammation resolution pathways and promising targets for biomarkers or therapy?
- What state-of-the-art technologies, methodologies, and approaches can be leveraged to advance research in inflammation resolution?
- What are barriers to understanding the role of inflammation resolution in diseases and conditions within the NIAMS mission?
- How can current knowledge and data in inflammation resolution be integrated to understand and improve the management of diseases and conditions within the NIAMS mission?
The community’s responses to the questions enriched the discussion. Although not all responses submitted in advance were discussed at the roundtable, NIAMS staff read each comment. The Institute greatly appreciates the community’s input.
1 Times are noted in approximate hours and minutes on the videocast. The link does not take the viewer directly to the timepoint in the videocast.
Presentation: Current Understanding and Major Cell Types and Factors Involved in Inflammation Resolution (Charles Serhan, 22:211)
The meeting began on November 16 with a welcome from the NIAMS Director, Dr. Lindsey Criswell, and the meeting co-chairs, Dr. Edward Botchwey and Dr. Katherine Fitzgerald. After the welcome, Dr. Charles Serhan presented on the current understanding of specialized pro-resolving mediators (SPMs), including the protectins, maresins, and D and E series resolvins. These lipids are produced by a number of different cell types during inflammation. Researchers have determined their structure and described the steps in their biosynthesis from essential fatty acid precursors. The SPMs have been shown to actively promote inflammation resolution via their interactions with G-protein coupled receptors found on the surface of target cells. Several functions have been reported for the SPMs, such as controlling infection and inflammation, stimulating tissue regeneration, and reducing pain. SPMs also reduce the magnitude and duration of the acute inflammatory response. Additional research on SPMs may lead to new treatments for chronic inflammatory diseases within the NIAMS mission.
Discussion: Key Mechanisms of Resolution of Inflammation (44:191)
Cell-cell interactions and immune networks
After the presentation by Dr. Serhan, the group discussed key cell types that are present during the resolution of inflammation. Some cell types have well known roles in the resolution process whereas the role for others is unclear. For example, macrophages are known to play important roles during inflammation resolution, such as clearing neutrophils and debris from sites of inflammation and recruiting adaptive immune cells. T regulatory cells have been shown to promote repair and regeneration after inflammation in muscle and other tissues. Additional research is needed to explore whether interactions between T regulatory cells and stem cells contribute to tissue regeneration during inflammation resolution. Participants expressed interest in learning more about how other cells within sites of inflammation might affect resolution. For example, although some types of dying cells, such as those undergoing apoptosis and necrosis, have been studied in the context of inflammation, less is known about the effect of other cell death mechanisms on inflammation and its resolution. The researchers also discussed the need to better understand the effects of senescent cells because those cells, and the factors they secrete, may impede resolution.
Age, gender, diet, and other variables
The group discussed a range of biological and environmental factors that may affect inflammation resolution. Research to understand the mechanisms of sex differences in autoimmune diseases such as lupus have revealed profound differences between neutrophils—immune cells that play an important role in inflammation resolution— from young women as compared to those from men of the same age. Sex differences also have been described with respect to the SPMs (e.g., in the biosynthesis of these mediators). The role of sex and gender are just beginning to be unraveled in NIAMS mission areas and more work is needed to understand potential relationships among sex-dependent factors such as hormones, immune cell functioning, and inflammation resolution.
In addition to sex and gender, participants mentioned several other factors, including diet, the microbiome, circadian rhythms, epigenetics, and aging, that could affect the resolution of inflammation. Diet has been investigated as a risk or protective factor for various diseases and may link to the SPMs due to production of these lipids from essential fatty acids. The microbiome also appears to play a role in inflammation resolution with dysbiosis linked to the production of pro-inflammatory mediators. The effect of circadian biology on inflammation resolution is a potential direction for further research. Investigators studying the effect of circadian rhythms have found that neutrophil functions vary depending on the time of day. Scientists also are studying the role of epigenetics in diseases within the NIAMS mission area. Further research is needed to investigate whether epigenetic changes that may occur during disease progression can influence the resolution of inflammation (e.g., how repeated bouts of inflammation that occur in diseases such as osteoarthritis may affect subsequent inflammation resolution). Finally, aging increases the risk for many diseases and has well-documented effects on the immune system. The meeting attendees agreed that the effects of aging should be an important consideration in designing studies of inflammation resolution.
Mechanisms of inflammation resolution
The group discussed a few potential biological mechanisms involved in inflammation resolution. For example, studies of the SPMs suggest that these mediators enhance the removal of cells and debris through metabolic reprogramming of macrophages. However, many gaps remain in understanding the mechanisms of resolution. For example, the mechanisms by which pro-resolving mediators foster tissue regeneration and healing remain unknown. Participants were also very interested in the mechanisms by which pro-resolving mediators might link to pain, which is associated with many inflammatory diseases and has profound effects on patients’ quality of life. In addition, more research is needed to identify mechanisms that might actively impede inflammation resolution. Understanding why resolution fails may provide new insights into diseases and conditions that are characterized by non-resolving inflammation.
Presentation: Lessons from Preclinical and Clinical Research on Inflammation Resolution (Thomas Van Dyke, 2:05:481)
Preclinical and clinical research on inflammation resolution in periodontal disease shows promise for the use of pro-resolving mediators to treat inflammatory diseases. In animal studies, treatment of periodontitis with exogenous SPMs resolved inflammation and stimulated healing and regeneration of damaged tissues. In clinical studies, SPMs reduced gingivitis in study participants and promoted regeneration in a few participants who also had periodontitis. To date, no clear signals that would raise concerns about the safety of SPMs have been observed in clinical studies. Interestingly, local administration of SPMs appears to have the systemic effect of increasing pro-resolving molecules in the serum. Furthermore, a study of the effects of SPM treatment in animals with periodontitis and cardiovascular disease (i.e., cardiovascular plaques) suggested that local treatment of periodontitis showed a systemic effect by reducing cardiovascular risk.
Discussion: Knowledge Garnered from Preclinical and Clinical Research (2:29:401)
Methods for identifying common or disease-specific targets or pathways involved in inflammation resolution
Following the presentation by Dr. Van Dyke, participants discussed cutting-edge technologies and methods to advance fundamental research on pathways involved in the resolution of inflammation. Many of the scientists mentioned combining “multi-omics” technologies (e.g., single-cell RNA sequencing, epigenomics, proteomics, lipidomics, metabolomics) with bioinformatics and computational biology to improve understanding of the spatial and temporal aspects of inflammation resolution in different tissues. In addition, cutting edge imaging techniques (e.g., live cell imaging) could shed light on key mechanistic details such as cell-cell interactions. The researchers underscored the importance of using immunoprofiling to understand which immune cells are present and what they are doing during inflammation and its resolution. Microbiome analysis could clarify the role of the microbiome dysbiosis in chronic inflammatory diseases. Participants also agreed that traditional experimental approaches, such as creating transgenic and knockout mice for genetic studies, are needed to advance research on the resolution of inflammation.
Relationship between the dynamics of biosynthesis of inflammation resolution mediators and clinical manifestations of inflammatory diseases
Participants touched briefly on the relationship between the biosynthesis of the SPMs and clinical outcomes, which has been studied in some diseases. Examples cited included research on the relationship between SPM levels and clinical outcomes in sepsis and atherosclerosis. Because the precursors of SPMs must be obtained from dietary sources, researchers also have studied how supplementation (e.g., with omega-3 fatty acids) affects SPM levels and disease outcomes.
Approaches to selectively turn on inflammation resolution pathways
The group spent some time discussing approaches to modulate inflammation resolution in experimental systems. Overall, they agreed that the choice of an approach to modulate inflammation resolution pathways is context dependent. Investigators will need to tailor their approach to the disease or condition they are studying. Participants also discussed several important considerations for designing studies of inflammation resolution. When using SPMs to stimulate resolution, researchers must decide which of those molecules is best suited to their research question since specific SPMs may be found in some tissues and organ systems but not others. The researchers also noted several possible options for delivering SMPs in experimental systems (e.g., via biological scaffolds and biomaterials). However, SPMs are not the only options for reducing inflammation, and whatever approach investigators choose, they will need to consider whether to use local versus systemic administration of pro-resolving mediators and when during the inflammatory process to introduce resolution mediators.
Presentations: Progress and Prospects for Inflammation Resolution in NIAMS Mission-relevant Diseases (John Varga, Na Xiong, Jennifer Elisseeff, Stuart Goodman, Jennifer Gordon, 09:311)
On November 17, the meeting resumed with five brief presentations on inflammation resolution research and research needs in the NIAMS mission areas.
Rheumatic diseases
Dr. Varga discussed the potential of inflammation resolution therapies for rheumatic diseases. Rheumatic diseases are systemic, chronic inflammatory diseases where failed resolution of inflammation is a key component. Genetic variation plays an important role in rheumatic diseases and the underlying immune response is abnormal. Changes in metabolic pathways also have been reported in these diseases. The genetic, immune, and metabolic changes seen in rheumatic diseases may potentially alter the resolution of inflammation in affected individuals. Research shows that macrophages and stromal cells play an important role in inflammation in rheumatic diseases. Current treatments, such as those that block cytokine signaling can have side effects and are not effective in all patients. Some of the anti-inflammatory treatments used to treat rheumatic diseases, such as glucocorticoids and methotrexate, also seem to have some pro-resolving functions. New treatment approaches that could help to resolve inflammation are needed. In this regard, studies are underway of agents, such as itaconate and metformin, that regulate macrophage metabolism.
Skin biology
Dr. Xiong described his work to understand the chemokine CCR27 and its receptor CCR10, which help to establish immune homeostasis in the skin. Experiments using mouse models in which CCR10 or CCR27 have been removed suggest that these molecules also suppress skin inflammation. Research in various skin disease models (e.g., psoriasis, alopecia areata) revealed that CCR27 expression is decreased in the model animals suggesting that loss of CCR27 contributes to disease progression. Addition of exogenous CCR27 in the disease models reduced skin inflammation and promoted resolution. Interestingly, CCR27 knockout mice had abnormalities in accumulation of circulating T cells and dysregulation of CCR27 in skin appeared to have systemic effects.
Tissue repair and regeneration
Dr. Elisseeff described her research on models of healing wounds (i.e., muscle wounds) and non-healing wounds (i.e., articular cartilage wounds). The goal of this work is to facilitate the development of immunotherapies that favor regeneration over inflammation. Healing and non-healing wounds are populated by different cell types and inflammatory mediators and have distinct local, regional, and systemic effects. Various systemic factors, such as infection and aging, affect wound healing. Dr. Elisseeff’s laboratory is also using data from single-cell analyses to map cell-cell communication on a single-cell basis and understand how individual cells work together in larger systems. These studies revealed that certain macrophage subsets have distinct effects on inflammation. They also showed that senescent cells have profound effects on other cells (e.g., triggering T cells to produce pro-inflammatory cytokines).
Musculoskeletal disorders
Dr. Goodman discussed the prospects for research on inflammation resolution in musculoskeletal tissues. After musculoskeletal trauma, acute inflammation helps to clear microorganisms and debris and promote repair and healing. However, chronic musculoskeletal inflammation has pathological effects that damage tissue physiology, form, and function. Several research opportunities and needs exist related to inflammation resolution. For example, database mining in acute and chronic inflammation could shed light on the differences between resolving and non-resolving inflammation. Longitudinal studies are needed to understand the natural history of inflammation and its resolution. Research on the temporal and spatial aspects of resolution could reveal important information about the biological changes occurring during the process at the organ, tissue, and single-cell level. Better animal and other models are needed to advance this research. Researchers also should think creatively about next generation therapeutic interventions (e.g., use of mesenchymal stem cells, vaccines, and small molecules).
Patient perspective
Dr. Jennifer Gordon shared her experience as a vasculitis patient and patient partner with the Vasculitis Foundation. In vasculitis, inflammation damages the blood vessels. It is usually treated with immunosuppressive drugs, many of which have side effects. Although she is in remission, she takes several medications to maintain control of the disease. Research is needed to understand sub-clinical disease activity, identify mechanisms involved in the acute versus chronic phase of disease, and improve quality-of-life for patients (e.g., reduce joint pain and fatigue). She noted that even individuals whose disease is considered well-controlled likely have active unresolved inflammation and could potentially benefit from targeted therapies that completely resolve inflammation.
Discussion: Understanding the Role of Inflammation Resolution in NIAMS Mission Relevant Diseases (42:021)
Models for translational studies of inflammation resolution
After the presentations, the group discussed various experimental models for studying inflammation resolution. Several animal models might be used to investigate pathways and mediators of inflammation resolution. For example, mouse models that exhibit a well-characterized progression to chronic unresolving inflammation (e.g., the DMX model of muscular dystrophy or various interferonopathy models) could be studied to investigate how the resolution of both inflammation and fibrosis are impaired. Animal models of sociological stress have been developed that could help to shed light on the connection between stress, which is increasingly recognized as a factor in the development of several diseases, inflammation, and inflammation resolution. Zebrafish are a unique tool for whole organism imaging that could be used to visualize specific immune and other cells during inflammation resolution. Organoid or microfluidic models, which allow researchers to incorporate specific mediators into their models, could also be used to investigate mechanisms. In vitro models, particularly those using cells from patients, may shed light on relevant pathways, specific mediators, or promising therapeutic targets.
While the group felt that animal models and in vitro systems are useful, they noted that these models have limitations. Human and animal immune systems are very different. Spontaneous resolution of inflammation occurs in many animal models, so those animals are typically better models of acute inflammation than chronic inflammatory diseases. It is difficult to find animal models that represent the heterogeneity of the pathobiology seen in patients. Due to cost constraints, researchers commonly use relatively young animals for research on inflammation resolution even though many chronic inflammatory diseases are associated with aging. Older animals might be better models for studying chronic inflammation since they exhibit fibrosis that is similar to fibrosis seen in the setting of chronic unresolved inflammation in patients. The group emphasized the need to understand the relationship between model systems and human disease and choose a model that best recapitulates the aspects of human biology being studied.
Applying inflammation resolution mediators as biomarkers and therapeutic targets in NIAMS-relevant diseases and conditions
Participants articulated the need to think carefully about possible uses of biomarkers and how different types of biomarkers could advance the development of pro-resolving therapies. Biomarkers are needed to identify individuals at risk of chronic inflammation. They could help to distinguish acute versus chronic inflammation and improve understanding of the acute to chronic transition. Biomarkers of subclinical inflammation and those that could predict severity of inflammation would also be useful. Biomarkers to assess the efficacy of pro-resolving therapy would facilitate the testing of new therapies. The discussion also highlighted the need to study longitudinal samples before and after clinical onset of disease. Consideration should be given to leveraging archived patient samples with detailed clinical phenotyping to study biomarkers for inflammation resolution. Participants stressed the importance of standardized procedures for patient phenotyping, sample collection, processing, and storage with uniform annotations. In terms of identifying new biomarkers, the researchers discussed strategies such as using various tools to compare resolving and non-resolving wounds.
Inflammation resolution mediators for the treatment and management of inflammatory diseases and conditions within the NIAMS mission
Participants agreed that research in patients will be needed to enable precision medicine. The group discussed several opportunities for clinical research related to the resolution of inflammation. For example, in the perioperative space, researchers might test the effect of pro-resolving mediators on outcomes such as time to discharge or recovery time after procedures such as orthopaedic surgery. The group also noted that the surgical setting might be a good model for inflammation that is driven by innate immunity as opposed to autoimmunity. To gain insights into inflammation resolution in the context of autoimmunity, researchers might study autoimmunity associated with cancer immunotherapy. It may be helpful to conduct studies in readily accessible tissues (e.g., skin) to quickly move the field forward. The group also noted that combination therapy, using pro-resolving mediators in concert with other types of treatments (e.g., anti-inflammatory agents) could be required, particularly for rheumatic diseases.
Discussion: Leveraging Knowledge in Inflammation Resolution to Improve Health (2:01:081)
In the final session, the group discussed barriers to research on resolution of inflammation as well as promising research opportunities. Investigators noted the need for more accessible tools to measure known pro-resolving mediators. Recently, questions have arisen in the field regarding the validity of the methodology for detecting SPMs in experimental and clinical settings. They also mentioned that the lack of resources for bio-manufacturing and administration of inflammation resolution mediators has been a barrier to research. The group identified a need for shared resources (e.g., human tissue samples, older animals) and standardized methods to study the resolution of inflammation and validate results.
The participants agreed that there are many opportunities to advance inflammation resolution research in NIAMS mission areas. Immunophenotyping of patients could be helpful for a range of studies. Research on molecules that already have been shown to dampen inflammation, such as adenosine, can be extended to explore potential linkages to pro-resolving mediators like the SPMs. The researchers noted opportunities to connect NIAMS-funded researchers with researchers studying inflammation resolution in other fields (e.g., cancer, cardiovascular disease). Several tissue mapping initiatives are underway (e.g., in musculoskeletal tissues) that could potentially shed light on mediators of inflammation resolution in NIAMS diseases.
In closing, the participants emphasized the importance of research on the resolution of inflammation. Current immune modulatory therapies take a significant toll on patients, including the cost of medications and the burden of treatment regimens. Discovering new ways to resolve inflammation completely could simplify treatment protocols and alleviate pain and fatigue. The participants were excited about the prospects for further research and new opportunities to make progress.
Participants
BOTCHWEY, Edward, Ph.D., Georgia Institute of Technology
CRONSTEIN, Bruce N., M.D., NYU Grossman School of Medicine
ELISSEEFF, Jennifer H., Ph.D., Johns Hopkins University
FITZGERALD, Katherine A., Ph.D., University of Massachusetts Medical School
FREDMAN, Gabrielle, Ph.D., Albany Medical College
GOODMAN, Stuart B., M.D., Ph.D., Stanford University Medical Center
GORDON, Jennifer, Ph.D., Volunteer, The Vasculitis Foundation, Excision BioTherapeutics
GRAVALLESE, Ellen M., M.D., Brigham and Women's Hospital
GREGUS, Ann, Ph.D., Virginia Tech
HSIAO, Edward, M.D., Ph.D., University of California San Francisco
HUTTENLOCHER, Anna, M.D., University of Wisconsin School of Medicine and Public Health
KAPLAN, Mariana J., M.D., National institute of Arthritis and Musculoskeletal and Skin Diseases
LORENZO, Joseph, M.D., UConn Health
ROTHLIN, Carla, Ph.D., Yale School of Medicine
SCANZELLO, Carla R., M.D., Ph.D., University of Pennsylvania Perelman School of Medicine
SERHAN, Charles N., Ph.D., D.Sc., Harvard Medical School
VAN DYKE, Thomas E., D.D.S., Ph.D., The Forsyth Institute
VARGA, John, M.D., University of Michigan Medical School
VILLALTA, Armando, Ph.D., University of California, Irvine
XIONG, Na, Ph.D., UT Health San Antonio
NIH/FDA
BELKIN, Alexey, Ph.D.
BOYCE, Amanda, Ph.D.
BURROWS, Stephanie, Ph.D.
CARTER, Robert H., M.D.
CAUGHMAN, Cindy, M.P.H.
CIBOTTI, Ricardo, Ph.D.
CRISWELL, Lindsey A., M.D., M.P.H., D.Sc.
DRUGAN, Jonelle K., Ph.D., M.P.H.
GOLDMUNTZ, Ellen, M.D., Ph.D.
KINDZELSKI, Andrei L., M.D., Ph.D.
LESTER, Gayle, Ph.D.
LUMELSKY, Nadya, Ph.D.
MANCINI, Marie, Ph.D.
MYERS, Sara, M.P.H.
NADADUR, Srikanth, Ph.D.
NGUYEN, Van T., Ph.D.
NICKS, Kristy, Ph.D.
NIKOLOV, Nikolay P., M.D.
PARK, Heiyoung, Ph.D.
ROTHERMEL, Annette L., Ph.D.
TAYLOR, James M., Ph.D.
WASHABAUGH, Charles, Ph.D.
ZHAO, Xiaoli, Ph.D.
ZHOU, Guofei, Ph.D.