Disorders of the Monocyte Macrophage System: Pathophysiological and Clinical Aspects

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Evidence-Based Oncology. Evidence-Based Diabetes Management. Compendia Alternative Payment Models. Clinical Pathways. Glucose Monitoring. Multiple Sclerosis. Pain Management. Parkinson Disease. Precision Oncology. Women's Health. CKD pathophysiology. Different immune and nonimmune conditions may cause the initial renal insult that is been influenced by both modifiable and non-modifiable risk factors.

This original damage causes several changes on renal function reducing the glomerular filtration rate, impairing the renal tubular hydroelectrolytic balance and damaging the glomerular filtration barrier. In a forward positive feedback, these events are able to lead to glomerulosclerosis, renal fibrosis and progressive loss of function.

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

The inordinate activation of the renin-angiotensin-aldosterone system RAAS is one of the major factors that can stimulate CKD progression [ 9 ]. Traditionally, RAAS used to be considered only as an endocrine system, whose major function was to maintain the blood pressure, even in situations of hypovolemia [ 16 ].

In the traditional description of RAAS, Renin, a hormone synthesized by the renal juxtaglomerular cells, promotes the conversion of angiotensinogen, produced in the liver, into angiotensin I Ang I. This peptide is further cleaved by angiotensin-converting enzyme ACE into its active form, the Angiotensin II Ang II , which, in turn, binds to its specific receptors AT1 in the adrenal cortex, resulting in the release of aldosterone.

Once released in the blood stream this mineralocorticoid steroid promotes renal and systemic vasoconstriction and tubular sodium conservation, leading to the elevation of blood pressure [ 9 , 16 ]. In spite of its first description, RAAS became much more complex in the recent years, after the identification of many novel components, such as the enzyme chymase, which exerts the same function of ACE, the biologically active peptides angiotensin III, IV, 1—9 and 1—7, and a number of different Ang II receptors AT2, AT4, among others [ 16 ].

Moreover, depending on which intracellular downstream system is activated by Ang II, different physiological responses can be triggered [ 16 , 17 ]. Ang II has been related to inflammation followed to chronic nephropathy developed by the enhancing of the immune response and favoring renal infiltration by leukocyte [ 18 , 19 ]. Additionally, there are growing in vitro and in vivo evidence that Ang II promotes cell proliferation and fibroblast activation, worsening the accumulation of EM and contributing to the development of renal fibrosis [ 18 , 20 , 21 ].

This was one of the first studies suggesting that the inflammatory process, including mononuclear cell infiltration and fibroblast proliferation was a final pathway common to different forms of renal injury, independent of its etiology. We currently know that inflammation exerts a key role in the pathogenesis of CKD, although the mechanisms by which this process is activated and perpetuated, even when the initial insult is not immune-mediated, remain unclear.

There is growing evidence that the activation of both cellular and humoral immunity is related to the progression of renal insufficiency and a worse prognosis in nonimmune-mediated CKD. Renal infiltration by macrophages has been demonstrated in a variety of human nonimmune-mediated renal diseases, such as diabetic nephropathy DN [ 26 ] and hypertensive nephrosclerosis HN [ 27 ].

Moreover, this phenomenon was also observed in different experimental models of CKD over the last years. Accordingly, the number of inflammatory cells in the renal interstitium closely correlates with the severity of nephropathy and with glomerular and tubulointerstitial lesions in these experimental models [ 28 , 29 , 30 ]. The increase of dendritic cells DCs in the renal parenchyma, in turns, is believed to indicate the spreading of inflammation from glomerular to the tubulointerstitial compartment, playing a pivotal role in the progression of both AKI and CKD [ 31 , 32 ]. Finally, cortical T-lymphocyte infiltration is a common finding in both genetic [ 33 ] and pharmacologically induced [ 34 ] DN in rodents.

In most of these studies, the amount of T-cells in the renal interstitium correlates positively with the progression of albuminuria, creatinine retention, and renal structural damage, as shown in Table 1 [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Corroborating these findings, a number of experimental studies showing significant evidence that anti-inflammatory treatment, as well as the knockout KO of specific pro-inflammatory genes can be effective to detain the evolution of nephropathy in different animal models of CKD, have been recently published, as shown in Table 2 [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].

Although the exact sequence of the inflammatory events in progressive CKD has not been completely elucidated yet, we are currently aware that, the activation of tubular epithelial cells, inordinate production of cytokines, activation of resident phagocytes and fibroblasts, as well as the transdifferentiation of these last into pro-fibrotic myofibroblasts, parallels renal leukocyte infiltration, from the early beginning of renal disease. Furthermore, these processes follow the evolution of CKD, becoming autonomic and leading to excessive production of EM and fibrosis [ 9 , 14 , 32 , 53 ].

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Macrophage in chronic kidney disease | Clinical Kidney Journal | Oxford Academic

The immune system IS is composed by a set of structures, cells, and processes that together enable an organism to recognize their self-elements from the foreign and potentially pathogenic ones, producing then, a physiological response consistent with the nature of the recognized element, which can be either a self-harmless protein or a dangerous bacterium [ 54 ]. As part of these systems, there are the so-called nonimmunological physical, chemical, and biological barriers and the immunological components itself, represented by innate and adaptive mechanisms of cellular and humoral immune response [ 54 , 55 ].

In a simplistic way, the IS is responsible for four different body functions. The first one is the immune tolerance, the property that allows the body to recognize self-cells, proteins, and other constitutive elements, producing a response of tolerance and preventing autoimmune reactions.

This particular state of IS unresponsiveness is also essential to ensure the regular fetal development during pregnancy and to allow the colonization of human skin, digestive tract, and vagina by beneficial microorganisms referred as microbiota [ 56 , 57 ]. The second and most well-known function of IS is the immunity itself. It is the ability to recognize foreign proteins and molecules, which may indicate the presence of invading microorganisms, such as bacteria or other parasites, and respond to these foreign elements with both cellular and humoral defenses, protecting the organism against infection [ 54 ].

Additionally, through its third property, immune surveillance, the IS patrols the body to recognize and destroy self-cells infected by virus or even constitutive cells that become cancerous or suffer phenotype alterations due to genetic mutations [ 54 , 55 ]. Finally, the last property of IS is the ability of self-controlling the immune response. Through a complex mechanism of feedback and cell-to-cell communication, involving a number of cytokines and cell-cytokine receptors, IS modulates its response, which can be either tolerance or immunity, according to the specific stimulus to which the organism is subjected to [ 54 ].

This property is known as immunoregulation and is of paramount importance, not only for the kidneys but also for the whole organism. The integrity of the epithelial tissue can be listed as one of the most important nonimmunological physical barriers against infection. The skin represents the largest organ of the human body and its main function is to delimit the organism, separating it and protecting it from the environment that surrounds it.

Of course, it is not an insurmountable insulation, since this would be incompatible with the maintenance of life: water, atmospheric gases, and ions are able to cross the epithelial barrier simply due to passive processes such as osmosis and diffusion or through active transmembrane transport. However, macromolecules, such as high-weight proteins or even whole cells are not able to transpose the barrier formed by epithelial tissue in a normal physiological situation, making the area covered by the intact epithelium protected from invasive pathogens.

Some virulent microorganisms can produce elements capable of puncturing or injuring the epithelial tissue, opening a gateway to the host organism. Certain strains of uropathogenic Escherichia coli UPEC , for instance, produce proteolytic enzymes, cytotoxic necrotizing factors, and numerous adhesive molecules adhesins as part of their invasion arsenal [ 60 ].

Pro-inflammatory M1 macrophages in CKD

UTI is a worldwide health problem that affects over 13 million of people each year in the US. It is currently the most common infection in adult females and, in nearly all cases, it is caused by a few strains of UPEC. Moreover, recurrent UTI may contribute to additional problems, including renal scarring, CKD, and an increased risk for developing bladder cancer [ 60 ].

Besides the presence of UPEC and the toxins produced by them in the urinary tract, there are evidence that proteinuria can itself cause injury to the renal and urinary epithelium. Since proteins are expected to be retained in the GFB, increased protein concentration in the urinary fluid is considered an irritating and pro-inflammatory factor for the tubular, ureteral, and bladder epithelium, leading to enhanced protein reabsorption by the tubular epithelial cells, overload of their catabolic capacity, leukocytes infiltration, and corruption of the integrity of the urinary epithelial barrier [ 54 ].

The intestinal and ureteral peristaltic movement and the flow of fluids like vomiting, diarrheal, or the urinary stream itself are also important physical barriers against infection, preventing the onset and permanence of microorganisms in the digestive system and in the lower urinary tract. In addition to these physical barriers, the maintenance of low pH in some body fluids is one of the chemical physiological strategies of greater prominence to avoid infections.

Accordingly, low stomach and urinary pH can destroy most of the parasitic organisms which, by chance, succeed in penetrating these systems [ 55 ]. The benefits of having the intestines, skin, and vagina occupied by specific strains of innocuous bacteria were once thought to be limited to the reduction of pathological colonization, due to the competition among the invaders and the resident flora.

Nowadays, we know that the microbiota lives in fact in a mutualistic symbiosis with our body, benefiting themselves and the host [ 54 , 55 , 61 ]. The integrity of our intestinal microbiota, for instance, is essential to the digestion of a number of food components, making the absorption of important nutrients easier. Moreover, the anaerobic bacilli that inhabit the vaginal cavity are responsible for the maintenance of acid pH in that region, since they produce lactic acid as an anaerobic respiration metabolite, keeping the vagina free of fungal colonization.

It is of note that the resident microbiota lives in a delicate balance with our IS. Its growth is controlled and limited by phagocytic cells and other elements of the IS, and the occurrence of imbalances in the property of immunoregulation, such as immunity reduction due to illness, immunosuppression, stress, or malnutrition, may lead to an exacerbated growth of microbiota population, which is potentially harmful for the human organism and should be controlled [ 54 , 61 ]. When the above mentioned nonimmunological natural barriers are overcome by pathogens or other irritative elements, the immune response is initiated through the inflammatory reaction, as an attempt to restore tissue integrity.

In case of infection, for instance, the elimination of invading microorganisms becomes a necessary condition for tissue repair. Inflammatory reaction depends on the action of specific blood cells called leucocytes. Under normal physiological conditions, there are around and 10, leukocytes per blood microliter, but these numbers significantly rise in the presence of an infection. Leukocyte classification.

Pathophysiological and Clinical Aspects

Leukocytes can be classified as myeloid or lymphoid cells, according to their hematopoietic origin, or as mononuclear or polymorphonuclear cells, according to the number of cellular nuclei and cytoplasmic granules they appear to have, in their mature circulating form, under light microscopy. This broadest category is composed by monocytes: phagocytic cells that give rise to both macrophages and dendritic cells; mast cells, which are mainly responsible for vasodilation on inflammatory processes; lymphocytes, the effectors of our specific immune response, and finally, the natural killer cells NK.

Leukocytes whose cytoplasm is rich in granules of enzymes and cytotoxic substances, such as reactive oxygen species, are generally called granulocytes.

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Basophils, eosinophils, and neutrophils can be called granulocytes. Macrophages and dendritic cells also have a considerable amount of granules in their cytoplasm; however, they are described as phagocytes, due to their ability to phagocyte invading microorganisms. All leukocytes are capable of producing a broad range of chemical mediators involved in the immune response generally called cytokines in response to lesions or to the presence of microorganisms. In addition to being responsible for the synthesis of these cytokines, leukocytes are also responsive to the action of these mediators, which promote, among other biological effects, leukocyte chemotaxis toward the inflammatory focus as well as its activation [ 32 , 54 , 55 ].

Cytokines are soluble glycoproteins, which may have autocrine, paracrine, or endocrine action. A fraction of these mediators have been at least partially described, however, there is still an almost infinite range of little known pro-inflammatory cellular signaling molecules, whose activity has not yet been fully established. As far as we currently know, once the nonimmune body barriers are overcome by a pathogen or a dangerous substance, a microscopic battle begins in the injured tissue.

The first line of defense of our immune system is the innate immunity, which comprises a group of cells, intracellular mechanisms, and chemical mediators, extremely conserved evolutionarily. Long before vertebrates first appeared on Earth, their primitive ancestors already had effective systems of immune cells recruitment, production of cytokines, activation of the complement cascade, identification of foreign elements through transmembrane and intracellular molecular pattern recognition receptors MPRR , inactivation of pathogens through the production of reactive oxygen species ROS , antimicrobial peptides and lytic enzymes, and, finally, removal of invader microorganisms through phagocytosis.

Although innate immune system is a nonspecific evolutionarily older defense strategy, it is a fast mechanism that comes into play immediately or within hours of the appearance of a foreign element in the body, initiating the inflammatory process [ 32 , 37 , 38 , 39 , 40 , 41 , 42 , 54 ]. After this first identification, local cells synthesize and release vasoactive mediators that promote vasodilatation and increase the local blood supply, causing heat and flushing; common features of inflammation.

The concomitant activation of resident innate immune cells also takes part in the process. Under physiological conditions, the most common kidney resident immune cells are tissue macrophages and dendritic cells.

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