Introduction
The urinary tract system consists of organs such as ureters, kidneys, urethra, and bladder. The lower urinary tract lies close to the gut, exposing it to an immediate influx of gut bacteria. However, among these organs, the bladder always remains largely free of infection. The bladder is resistant to microbial colonization because of its antimicrobial components secreted from the urothelium and the anatomical design leading to the development of bladder resistance towards microbial colonization.
The apical area of the urothelium consists of uroplakin plaques and is composed of mucus that does not promote the microbial adherence and invasion. The urothelium of the bladder stores urine for prolonged periods and protects the underlying tissue from toxic constituents and urine. The whole urinary system and bladder must constantly maintain the integrity of urothelium. Hence, the immune responses of the urinary system are regulated to minimize the damage by controlling the inflammation in an orderly manner.
What Is the Response of the Immune System in a Urinary Tract Infection?
When bacterial infections bypass the defenses of the urinary tract, the immune system initiates a rapid and vigorous response. Some pathogens like uropathogenic Escherichia coli (UPEC) still infect and colonize the urinary tract despite the responses from the immune system. UPEC is responsible for about 80 percent of urinary tract infections. This pathogen is believed to originate from the intestines because these bacteria are inhabitants of the gastrointestinal tract microbiome. UPEC infects the urinary tract since it multiplies rapidly in the urine and overcomes many natural barriers to infection. It also persists within the bladder epithelium in an inactive state for longer periods, leading to recurrent or chronic urinary tract infections.
What Are the Cellular Components Of Innate Immune Response Towards a Urinary Tract Infection?
-
When uropathogens invade and enter the bladder, the first host cells that encounter them are the superficial bladder epithelial cells (BECs). These cells contain receptors for various bacteria and their products, and they first form a tight and highly impermeable barrier.
-
Soon after an infection, a large amount of secretion of the interleukin -6 (IL-6) is secreted in the urine, indicating evidence of a pattern recognition receptor activity.
-
These cytokines are the products of Nod-like receptor/caspase-1 and Toll-like receptor 4 (TLR4) activity.
-
Along with other mediators of inflammation secreted by the bladder epithelial cells, these cytokines cause an influx of immune cells to the epithelium to counter the challenge of bacterial invasion.
-
The BECs counter this response by secreting several factors that can directly kill the bacteria. One such factor is cathelicidin LL-37.
-
The mRNA expression of cathelicidin LL-37 rose while the epithelial cells get stimulated within 5 minutes with uropathogenic Escherichia coli.
-
Antimicrobial peptides found in the urine, such as β-defensin, mainly originate from the kidney epithelial cells than the BECs.
-
These antimicrobial peptides contribute to neutrophil recruitment in the bladder and cytokine production.
What Is the Role of Bladder Epithelial Cells?
-
The bladder epithelial cells produce cytokines and chemokines that help form a highly effective barrier against infection and function as an antimicrobial agent source.
-
They also regulate the volume of the bladder to accommodate the urine. BECs contain large volumes of fusiform vesicles.
-
When the urine enters the bladder, these fusiform vesicles undergo exocytosis into the plasma membrane in an AMP manner to provide the membranes required for the expansion of the bladder.
-
After voiding, for the bladder volume to contract, the fusiform vesicles again form by internalization of the membrane.
-
The UPEC utilizes uses a variety of virulence factors to gain entry into the BECs. After binding to the surface of BECs, the UPEC triggers a local burst of cyclic AMP, undergoing exocytosis of the fusiform vesicles at the adherence site.
-
BECs have a defence system capable of sensing outside bacteria and initiating mechanisms to put the bacteria out of their refuge. This activity is initiated when the bacteria enters and gets triggered by the TL4 localized in the vesicles encasing the bacteria.
What is the Response of Neutrophils, Mast Cells, and Macrophages?
-
When an infecting bacteria enter the body, mast cells, macrophages and neutrophils form the first earliest immune response to target the foreign body in the bladder.
-
Once the inflammatory response is triggered, these immune cells eliminate the bacteria.
-
While the bacteria enters, the pattern recognition receptors get stimulated. The bladder epithelial cells produce IL-8, leading to the recruitment of neutrophils into the bladder lumen and epithelium, where the infecting bacteria is found.
-
The recruited neutrophils exit the blood vessels, migrate toward the lamina propria and penetrate the basement membrane.
-
Even though the migration of neutrophils happens in response to IL-8, the key of its penetration towards the basement membrane also happens due to its ability to express metalloproteinase-9.
-
When the neutrophils cross the membrane, they bypass multiple epithelial cell layers before they reach the superficial epithelium.
-
The superficial epithelium is the final cell layer of the epithelium before the neutrophils enter the bladder lumen.
-
The recruitment of neutrophils in the urinary tract is often fast and equal to the bacterial load.
-
Within two hours of a bacterial infection, the phagocytic cells arrive and peak within six hours. As the bacteria clears, their numbers decrease.
-
The antibacterial activity of the neutrophils in the urinary tract mainly consists of the cell's capability to engulf and intracellularly degrade the bacteria.
Conclusion
Studies recently revealed that when bacteria enter the bladder, the bladder epithelial cells, macrophages, and mast cells activate a coordinated multicomponent immune defense program. The cells' individual responses attack the invading pathogen and recruit neutrophils to the bladder to clear the invading pathogens. When the neutrophils are recruited in large numbers into the bladder, they work efficiently in eliminating the invading bacteria from the urinary tract. However, these neutrophils are cytotoxic (toxic to living cells) toward the surrounding tissues. Because of this, the damage during urinary tract infections is mainly due to the recruited neutrophils. Each bladder resident cell type has separate mechanisms to reduce the activity or neutrophil numbers in the inflamed site.
