General Pathology 101: Resolution of Inflammation

Foreword

Inflammation is a vital reaction mechanism to threats, and it is part of a beneficial defense system that has evolved and been conserved evolutionarily over thousands of years. But why is this process associated with diseases? While inflammation is primarily protective and helps maintain tissue equilibrium, uncontrolled inflammation can become detrimental, leading to the progression of chronic inflammatory diseases. This 101 series aims to provide a comprehensive understanding of the inflammatory process by emphasizing its historical context, intricate mechanisms, and events that will determine its end or the development of diseases. Through six captivating chapters, readers will obtain a holistic perspective on inflammation and its significance in health and disease.

This 101 series is divided into six articles including:

1. General Pathology 101: Inflammation - Historical Perspectives

2. General Pathology 101: Inflammatory Cells and Mediators

3. General Pathology 101: Inflammatory Cells Recruitment and Clearance

4. General Pathology 101: Resolution of Inflammation

5. General Pathology 101: Acute vs. Chronic Inflammation

6. General Pathology 101: Inflammatory Diseases

General Pathology 101: Resolution of Inflammation

Inflammation is a process that must be strictly regulated to ensure the appropriate intensity and duration of the response, enabling the removal of triggering factors and the restoration of the integrity of tissues and their functions. Successful inflammation comes to an end, and the process that triggers this end is called the resolution of inflammation. The resolution of the inflammatory response is an active, well-coordinated process controlled by endogenous mediators that regulate cellular and molecular events necessary for effective tissue restoration. Defects in this control are associated with exacerbated and prolonged inflammation, in addition to the development of chronic and autoimmune diseases. In this section, the main aspects of the resolution of inflammation will be described, including the mechanisms of cellular processes (apoptosis, efferocytosis, cell polarization) and mediators involved in the resolution process (pro-resolving mediators).

Resolution of Inflammation: Historical Perspective

For many years, the prevailing belief held that the passive dissipation of pro-inflammatory mediators at inflammatory sites was responsible for the cessation of the inflammatory response. However, it is now evident that biochemical pathways and cellular mechanisms can counter-regulate inflammation and promote resolution. Today, there is a mounting body of evidence indicating that resolution is an active process, contrary to the once widely accepted passive view. This paradigm shift has paved the way for new therapeutic approaches in the treatment of inflammatory diseases (Serhan et al., 2007).

In the past, ancient medical encyclopedias had introduced the notion of resolution into their manuscripts; for instance, the concept of "resolvent mollificants" was presented in the medical encyclopedia Canon of Medicine in the 11th century. However, there was no clear understanding of what constituted a resolvent and the mechanisms behind it. Towards the end of the 19th century, Elie Metchnikoff introduced important concepts based on cellular events and emphasized the key role of leukocytes in phagocytosis (Figure 1), both in host defense and in the maintenance of tissue homeostasis, thus laying the foundation for further studies (Medzhitov, 2010). More recently, the second edition of Robbin & Cotran's renowned pathology textbook provided a scheme that depicts inflammatory exudate resolved versus exudate reorganized, introducing the notion of precise cellular events involved in resolution (Panigrahy, Gilligan, Serhan, & Kashfi, 2021). Pioneering studies that illuminated the pivotal role of cellular mechanisms in resolving inflammation were conducted by Savil et al. in 1989 (Savill, Henson, & Haslett, 1989; Savill, Wyllie, et al., 1989). These findings demonstrated the critical role of macrophages in clearing apoptotic cells within inflamed tissues. A few years later, in the fifth edition of Robbins Pathologic Basis of Disease in 1994, Cotran et al. introduced the notion of complete resolution as the ideal outcome of inflammatory responses and attributed the failure of resolution as a potential outcome of chronic inflammation (Cotran, 1994).

Figure 1: Elie Metchnikoff and his drawings of bacterial phagocytosis by macrophages and neutrophils (Kaufmann, 2008).

In parallel to these findings related to cellular mechanisms of resolution, molecules displaying pro-resolving effects were being discovered. Back then, as the concept of resolution of inflammation did not exist as we know it nowadays, many of these molecules were designated only as anti-inflammatory molecules due to their described effects on inflammation control. Nowadays, it is known that many anti-inflammatory compounds may also have pro-resolution properties. One of the first molecules to be described in the literature was Annexin A1 (AnxA1), in 1979 (Flower & Blackwell, 1979). AnxA1 is a glucocorticoid-induced protein, and many of the anti-inflammatory actions of glucocorticoids (an important class of anti-inflammatory drugs) may be attributed to the AnxA1 effects (Sugimoto, Vago, Teixeira, & Sousa, 2016).

A few years after the discovery of AnxA1, an important series of lipid biologically active compounds, the lipoxins, were described by Serhan et al. (Serhan, Hamberg, & Samuelsson, 1984). Although discovered in the early 1980s, it was only in the 2000s that the pro-resolving activities of the lipoxin series were recognized and functionally characterized. Lipoxins have the ability to inhibit neutrophil infiltration and recruit macrophages to the inflammatory site, in addition to inducing the removal of cellular debris, inducing tissue repair/regeneration. Also, other lipid mediators derived from n-3 polyunsaturated fatty acids (PUFA), resolvins, were initially described in the year 2000 (Serhan et al., 2000). Since then, other lipid mediators have been discovered, such as maresins and protectins. The set of pro-resolving lipid mediators, including lipoxins, resolvins, maresins and protectins, is now collectively referred to as “specialized pro-resolving mediators” (SPMs).

Table 1: Timeline for resolution of inflammation (Serhan, 2011).

Over the past few decades, we have gained a deeper understanding of the mechanisms and mediators that govern the resolution of inflammation. Extensive studies in preclinical animal models have laid a robust foundation for comprehending the resolution process and identifying novel pro-resolving molecules. A growing body of research is dedicated to developing new medications with the goal of accelerating the resolution process and treating inflammatory diseases, including debilitating conditions such as chronic and autoimmune diseases.

Clinical studies have been undertaken to assess the effectiveness of molecules analogous to pro-resolving mediators (Serhan, Libreros, & Nshimiyimana, 2022). The more we comprehend the mechanisms behind inflammation resolution, the closer we come to the widespread therapeutic application of these mediators, potentially revolutionizing the treatment of inflammatory diseases.

Key Steps of the Resolution of Inflammation

The resolution of inflammation is an orchestrated and active process, involving mediators and cellular events with the purpose of controlling inflammation and to restore tissue homeostasis. Proper resolution of inflammation involves some key steps: i) catabolism of pro-inflammatory molecules, ii) elimination of inciting stimulus with further cessation of polymorphonuclear (PMN) cell recruitment, iii) induction of PMN apoptosis, iv) non-phlogistic monocyte influx and differentiation to macrophages, v) removal of apoptotic PMN (efferocytosis), vi) macrophage switch from a pro- to an anti-inflammatory /pro-resolving phenotype, and vii) production of pro-resolving mediators (Sugimoto, Vago, Perretti, & Teixeira, 2019). Thus, an inflammatory response is resolved by a series of crucial events that balance and control inflammation to restore tissue homeostasis (Figure 2).

Figure 2: Key steps for proper resolution of inflammation (Vago, Amaral, & van de Loo, 2021).

Catabolism of Inflammatory Mediators

Several regulatory mechanisms occur after removal of the insulting agent in order to limit the infiltration of inflammatory cells and prevent further tissue damage. As a way to counter-regulate pro-inflammatory signaling pathways, regulatory molecules are produced and released (such as anti-inflammatory cytokines, gene regulators, catabolic enzymes, etc.) that dampen the production or inactivate pro-inflammatory mediators (Alessandri et al., 2013). Thus, cytokine, chemokine, eicosanoid, and other inflammatory mediators are regulated, or their activity modified, to further limit inflammation and the infiltration of inflammatory cells. The breakdown of complex molecules into simpler ones is called catabolism and this process plays a very important role in the resolution of inflammation. Enzymes like proteases can cleave cytokines and chemokines, rendering them inactive. Additionally, cytokine receptors on target cells can internalize and degrade cytokines and chemokines as part of the signaling termination process (Bennett, Fox, & Signoret, 2011). Lipid-derived inflammatory mediators such as eicosanoids, can also be catabolized by enzymatic processes. For example, prostaglandins can be inactivated through enzymatic conversion by 15-hydroxyprostaglandin dehydrogenase. Leukotrienes can be enzymatically metabolized by enzymes like leukotriene hydrolase or further converted to less active derivatives (Dennis & Norris, 2015). Other inflammatory mediators like reactive oxygen species (ROS), including hydrogen peroxide (H2O2) can be catabolized by antioxidant enzymes. For example, catalase or glutathione peroxidase enzymes can break down H2O2 into water and oxygen (Juan, Perez de la Lastra, Plou, & Perez-Lebena, 2021). By removing an inciting agent and stopping pro-inflammatory mediator signaling, the recruitment of inflammatory cells to inflammatory sites can be attenuated and eventually stop, preparing the ground for subsequent events of inflammation resolution. Furthermore, other WBCs can also be determined in a complete blood count test, including lymphocytes, monocytes, eosinophils, and basophils [Table 1]. For example, increased numbers of eosinophils (eosinophilia) in the blood are associated with allergic reactions and parasitic infections while high lymphocyte count (lymphocytosis) typically rises after infection conditions (George-Gay & Parker, 2003).

Inhibition of Additional PMN Recruitment

The accumulation of leukocytes during the inflammatory response (Figure 3) depends on the balance between the number of cells recruited into the tissue and the frequency of cells that are eliminated or leave the tissue (Alessandri et al., 2013). Furthermore, it is important that leukocyte recruitment comes to an end. The reduction of inflammatory mediators at the site of inflammation is a crucial process to inhibit the recruitment of additional leukocytes, such as PMN. After elimination of the insulting agent by recruited cells during the initial phase of inflammation, the removal of these infiltrated leukocytes is essential for inducing resolution of the inflammatory response (Watanabe, Alexander, Misharin, & Budinger, 2019). Essentially, inflammatory cells can be eliminated by systemic re-circulation, lymphatic drainage or local cell death and removal by efferocytosis (Alessandri et al., 2013; Schwager & Detmar, 2019). Different forms of cell death, based on morphological, molecular, and functional criteria have been described, such as apoptosis, necrosis, autophagy, pyroptosis, necroptosis, and NETosis (Shen, Shao, & Li, 2023) but apoptosis has been reported as the main type of cell death associated with resolution.

Figure 3: Spatial cellular accumulation in the tissue following an inflammatory insult (Serhan et al., 2007).

PMN Apoptosis

Apoptosis is a predominant mechanism of cell death during a self-limited inflammatory response (Alessandri et al., 2013). In the context of resolution, apoptosis is considered a "clean" and "desired" form of cell death because it keeps cellular contents within membranes without causing amplification of the inflammatory process (D'Arcy, 2019). Other types of non-apoptotic cell death occur frequently during inflammation, such as NETosis and necrosis, but can contribute to the amplification of inflammation because intracellular contents can be released causing tissue damage (Cahilog et al., 2020). NETosis is a type of neutrophil cell death known as neutrophil extracellular traps (NETs), formed by the exposure of DNA fibers and granule proteins by neutrophils to capture, neutralize, and destroy microorganisms (Rosales, 2018). Necrosis is a type of cell death associated with loss of plasma membrane integrity and release of intracellular contents (D'Arcy, 2019).

During apoptosis, several proteases known as caspases begin an intracellular digestion process, culminating in the fragmentation of the entire cell and forming the so-called apoptotic bodies, which are vesicles containing digested cellular components from the dying cell. This process is finely regulated and allows the intracellular content to be removed from the inflammatory site without generating additional damage to the tissue (D'Arcy, 2019). When the cells are dying by apoptosis, apoptotic bodies are released to the extracellular compartment and are captured by professional phagocytes, including macrophages and dendritic cells, by a process called efferocytosis (deCathelineau & Henson, 2003).

Efferocytosis

Efferocytosis is a process that plays a fundamental role in the resolution of inflammation and it is mainly mediated by macrophages (Watanabe et al., 2019). During efferocytosis, macrophages recognize apoptotic cells at the site of inflammation, clearing these cells from that site, contributing to the return of the tissue to its natural state (Lin et al., 2020). Efferocytosis begins through the recognition of “find-me” molecules that are released by apoptotic cells, inducing the recruitment and migration of macrophages towards the direction of the dead cell. Once in contact with the apoptotic cell which exposure “eat-me” signals and promote specific recognition by the macrophages, macrophages change their conformation, encompassing the dead cell and cellular debris (engulfment), which will be degraded intracellularly [Figure 4] (Boada-Romero, Martinez, Heckmann, & Green, 2020). Clearance of apoptotic cells prevents tissue exposure to harmful intracellular contents, which could prolong the inflammatory response. Disturbances in the clearance of apoptotic cells have been implicated in the progression of chronic and autoimmune diseases, such as systemic lupus erythematosus (Zhang, Wang, Ding, & Liu, 2022). For this reason, additional recruitment of monocytes from the bloodstream to inflammatory sites appears to be a critical step in acute inflammation, allowing the clearance of apoptotic cells by macrophages through efferocytosis, with an orderly progression toward resolution (Watanabe et al., 2019).

Figure 4: The main steps involving the efferocytosis process (Liu, Liu, & Deng, 2023).

Macrophage Polarization

Successful efferocytosis can stimulate the reprogramming of macrophages from inflammatory (M1) to anti-inflammatory (M2) phenotypes, also called classical- and alternatively-activated macrophages, respectively (Murray, 2017). Pro- and anti-inflammatory macrophages exhibit distinct molecular markers and functions (Figure 5). Alternatively-activated macrophages produce anti-inflammatory and pro-resolving mediators (e.g., IL-10, TGF-b, resolvins, maresins), which stimulate inflammation resolution and tissue repair (Watanabe et al., 2019). In fact, the phenotypic changes of macrophages during inflammation are considered another key event of the resolution process. Macrophages (especially alternatively activated ones) are key components in the repair of inflamed and injured tissues. These macrophages, in addition to removal of apoptotic cells and production of anti-inflammatory and pro-resolving mediators, also regulate the remodeling of extracellular matrix components and stimulate collagen synthesis, regulate the formation of new blood vessels, restoring the oxygen supply in healing wounds, ultimately leading to complete structural and functional recovery of the tissue (Watanabe et al., 2019).

Figure 5: Macrophage polarization phenotypes, their markers, and main functions (Dias et al., 2022).

Pro-resolving Mediators

As systematically investigations into the molecular basis of inflammation and its resolution occurred, soluble molecules capable of inhibiting the pro-inflammatory process and inducing cellular events of resolution was identified (Flower & Blackwell, 1979; Serhan et al., 1984). Currently, resolution is defined as a complex process orchestrated by a large panel of molecules known as pro-resolving mediators. These mediators act in the main cellular and molecular steps of resolution and are quite diverse in nature, including lipid mediators (e.g., lipoxins, protectins, resolvins, and maresins), proteins and peptides (e.g., AnxA1 and IL-10), gaseous mediators (e.g., H2S and CO), and others (Sugimoto et al., 2019). Pro-resolving mediators can be produced locally or at distant sites, followed by their systemic release and extravasation to sites of inflammation. Although the knowledge and characterization of pro-resolving molecules have made considerable progress in recent decades, several mediators remain unknown and more studies should be conducted.

Annexin A1 (AnxA1)

AnxA1 is an endogenous pro-resolving mediator, first characterized as a glucocorticoid-induced protein, which was identified in 1979 by Flower and Blackwell (Flower & Blackwell, 1979). AnxA1 is effective on phospholipase-A2 (PLA2) inhibition and prevention of eicosanoid synthesis. AnxA1 was shown to be beneficial in the control of several inflammatory diseases in preclinical models, including arthritis (Galvao et al., 2017), infectious diseases (Tavares, Melo, Sousa, & Teixeira, 2022), cardiovascular diseases (de Jong, Leoni, Drechsler, & Soehnlein, 2017) and neurological disorders (McArthur et al., 2016). AnxA1 has been described to regulate inflammation by triggering neutrophil apoptosis and its removal by efferocytosis, as well as reducing the production of pro-inflammatory mediators (Sugimoto et al., 2016). These effects are associated with both AnxA1 and synthetic peptides generated from the N-terminal portion of this protein, particularly the Ac2-26 peptide (Sugimoto et al., 2016). Furthermore, translational studies (from basic research into clinical research in humans) have been conducted in order to understand the biological activities of this molecule in humans (Perucci et al., 2017).

Specialized Pro-resolving Mediators (SPMs)

Lipid mediators termed as specialized pro-resolving mediators (SPMs) derived mainly from the omega-3 essential fatty acids eicosapentaenoic acid (EPA), n−3 docosapentaenoic acid (n-3 DPA) and docosahexaenoic acid (DHA) (Serhan, 2017). These mediators are central in controlling immune responses and limiting inflammation. SPMs are classified into four main families: resolvins, protectins, maresins, and lipoxins. However, different from other SPMs, lipoxins are derived from arachidonic acid (AA), and their synthesis involves a series of enzymatic reactions that transform AA, a polyunsaturated omega-6 fatty acid, into lipoxin A4 (LXA4) or lipoxin B4 (LXB4) (Ryan & Godson, 2010). Interestingly, AA also serves as a precursor for several types of pro-inflammatory eicosanoids, including thromboxane, prostaglandins, and leukotrienes (Dalli et al., 2023) [Figure 6].

Figure 6: Bioactive lipid mediators (Dalli et al., 2023).

Lipoxins were the first lipid mediators demonstrated to inhibit leukocyte recruitment and promote apoptosis and efferocytosis (Serhan et al., 2000). Overall, endogenous SPMs have been described to be important mediators of resolution of inflammation in pre-clinical studies preventing excessive PMN infiltration, downregulating pro-inflammatory signals, and enhance the active clearance of pathogens and death cells by macrophages (phagocytosis and efferocytosis, respectively) (Serhan, 2014). SPMs also help restore tissue integrity and function, which is essential for resolving inflammation and preventing tissue damage and chronic inflammation. SPMs represent a class of pro-resolving mediators that have advanced significantly in the translational area in the past few years, especially regarding their detection and quantification in human samples (Jaen, Sanchez-Garcia, Fernandez-Velasco, Bosca, & Prieto, 2021; Perucci et al., 2017; Serhan, 2017). Understanding the synthesis and actions of these specialized pro-resolving mediators may have significant implications for the development of new treatments and interventions in the field of inflammation and immune regulation.

Future Perspectives and Pharmacological Therapy

There is growing interest in using these natural resolution pathways as therapeutic strategies for diseases involving acute and chronic inflammation. It is essential, therefore, to clarify the role of pro-resolving mediators in human host defense and inflammation regulation. Therefore, it is important that research in this area continues to advance. The figure below (Figure 7) illustrates two possible scenarios during an ongoing inflammatory response (1,3) and their outcomes (2,4,5) (Perretti, Leroy, Bland, & Montero-Melendez, 2015):

Figure 7: Time phase engagement of pro-resolving mediators (Perretti et al., 2015).

1. Inflammation is a protective and physiological response that, when successfully controlled in magnitude and time, is self-limited and induces tissue repair.

2. An effectively mounted inflammatory response entails the activation of pathways that safely terminate inflammation, protecting the injured tissue and promoting healing.

3. An excessive response to inflammatory stimuli can culminate in detrimental consequences and result in extensive tissue injury.

4. A failure in resolution process can extend in time the actions of pro-inflammatory mediators resulting in persistent (nonresolving) or chronic inflammation.

5. The activation of endogenous pathways of resolution through novel resolution-based therapeutics (pharmacological resolution) may restore tissue structure and function and return to homeostasis efficiently.

The development of new therapeutic strategies focusing on resolution will allow the development of alternative drugs enabling doctors to intervene more effectively in the control of chronic inflammatory pathologies. There are distinct approaches where mediators, targets and resolution processes can be explored in order to establish resolution as a therapeutic target. Examples of these innovative therapeutic strategies can be based on augment of pro-resolving mediators through dietary supplementation, design of molecules that mimic endogenous pro-resolving mediators, development of compounds that target pro-resolving receptors, and activation of endogenous pro-resolving pathways (Perretti et al., 2015). These strategies appear promising since most endogenous pro-resolving mediators are subject to inactivation in the body, mainly through enzymatic processes and metabolic transformations. To provide an insight into the concentrations of these mediators in humans, Figure 8 illustrates the spatial distribution of selected pro-resolving mediators found at bioactive concentrations in the human body.

Figure 8: Identification of SPMs at bioactive levels in humans (Serhan, 2017).

Therapeutic strategies focusing on resolving processes may represent a viable option for complex diseases that are currently poorly managed, often associated with high mortality rates or diminished quality of life. Conditions such as infectious, autoimmune, and degenerative diseases are examples of these challenging conditions. For instance, sepsis, a life-threatening infectious disease, associated with intense local and systemic inflammation and multiorgan damage (Jarczak, Kluge, & Nierhaus, 2021). Despite therapeutic advances in recent decades, sepsis is still the major cause of death among critically ill patients, contributing to 1 in 3 deaths of hospitalized patients (Liu et al., 2014). Classical anti-inflammatory therapies, such as glucocorticoids, are effective in reducing mortality rates in septic patients, but the long-term consequences and potential irreversible tissue damage associated with sepsis underscore the need for a more comprehensive approach (Liang et al., 2021). The control of leukocyte activation and trafficking, together with the efferocytic properties shared by pro-resolving mediators, represent characteristics that can benefit patients with sepsis, regulating the inflammatory response, inducing tissue repair, and reducing the chances of multiple organ failure. The use of pro-resolving mediators may be useful adjuvant pharmacological therapies to antibiotics in the context of infectious diseases.

Another example are autoimmune disorders such as systemic lupus erythematosus (SLE). SLE is a chronic disease characterized by a dysregulated immune system that mistakenly attacks healthy tissues and organs, causing widespread inflammation and tissue damage in the affected organs. SLE has been associated with impaired ability of leukocytes to recognize and eliminate dead cells and cell debris (defective efferocytosis) (Mahajan, Herrmann, & Munoz, 2016). A pro-resolving therapy in the context of SLE could possibly reverse the defective efferocytosis, reducing the tissue damage associated with this impairment and consequently inflammation.

Numerous neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, and Multiple sclerosis are inflammatory conditions of the central nervous system (Stephenson, Nutma, van der Valk, & Amor, 2018). These diseases have also been implicated with defective efferocytosis (Zhang et al., 2022). Pre-clinical studies have shown that pro-resolving mediators like SPMs are able to cross the blood-brain barrier, inhibit the activation of immune cells of the central nervous system (microglia), and decrease induced markers of inflammation (Ponce et al., 2022). These examples highlight the importance of exploring the resolution field as well as the development of therapeutic alternatives based on resolution that can serve as an innovative opportunity for the clinical management of complex pathologies with a great need for new therapeutic options.

Conclusion

The discovery of the inflammatory process, as well as its main players, exposed that unraveling the intricacies of this biological phenomenon demanded several decades of dedicated research. While the understanding of classical inflammatory mediators and cells is better understood, the focus on inflammation resolution, along with the identification of pro-resolving molecules and cellular mechanisms of resolution, is comparatively new. Although it is a relatively new concept, it is now known that the resolution of inflammation is an active process evoked by specific classes of pro-resolving mediators, which differ from classical anti-inflammatory molecules due to their ability to stimulate specific molecular and cellular programs. It is important to highlight that the enormous complexity of the inflammatory system can also be reflected at the level of pro-resolution pathways. Despite notable progress in this domain, our comprehension of inflammation resolution merely scratches the surface, and other new molecular and cellular players will likely be identified and defined in the near future. To move this field forward, it is extremely important that the triggering pathways for these pro-resolution events are defined for each tissue or disease, as these events can be specific. Such knowledge would be fundamental in the development of pro-resolution-based therapeutic strategies to treat complex chronic inflammatory diseases in humans, thus advancing this field forward.

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