Positive and negative regulations of innate and inflammatory responses and their effects

In this article, I briefly explain the positive and negative regulatory mechanisms of innate and inflammatory responses and their effects.

Table of Contents

Responses of Innate immunity

Innate immune responses have vital roles in annihilating infections. These responses eliminate the invading pathogen by phagocytosis or cytotoxicity. Secondly, the cells of innate immunity secrete different cytokines depending upon the nature of the receptors they engage. The cytokines then play their role in advising adaptive immunity to mount the required immune response.

However, if the innate immune responses are not controlled properly, they can have adverse effects. If various normally beneficial mediators are overproduced with uncontrolled local or systemic responses, it will ultimately lead to illness and death. Thus, careful regulation of innate and inflammatory responses is needed to minimize the harmful responses. There are positive and negative regulatory mechanisms controlling the innate and inflammatory responses.

Positive mechanisms regulating the innate and inflammatory responses

A diverse range of positive regulatory mechanisms helps to increase the protective functions of the innate and inflammatory responses. Many signaling pathways work together downstream multiple pattern recognition receptors (PRRs) to generate an elevated response.

RNA of the Dengue virus is recognized by pattern recognition receptors TLR 3, RIG 1, and MDA 5. The merging of signals from these three pathways increases the productivity of protective cytokine.

An example of positive feedback regulation can be considered when the cytokines IL-1β and TNF-α are initially produced when PAMP (pathogen-associated molecular patterns) or DAMP (damage-associated molecular patterns) binds to PRRs. They activate pathways downstream of TLRs (toll-like receptors) and induce more of themselves.

Negative mechanisms regulating the innate and inflammatory responses

Negative regulatory mechanisms are activated to control the adverse effects of uncontrolled innate and inflammatory responses. Many proteins have an increased state of activity following PRR signaling feedback to hinder steps in the signaling pathways downstream of the pattern recognition receptor (PRR).

The continuous exposure of macrophages to the TLR4 ligand LPS leads to the production of antimicrobial and pro-inflammatory mediators. This is followed by the induction of inhibitors, thus blocking the macrophage response to LPS. This is called LPS tolerance or endotoxin tolerance, which minimizes the possibility of septic shock resulting from the continuous exposure to LPS from a bacterial infection.

The cytokines, TNF-α and IL-1β, induce the production of a receptor-like protein, or a soluble receptor, that attaches to the circulating cytokine molecules. Thus, averting them from acting on other cells. In addition the anti-inflammatory cytokine IL-10 promotes wound healing by inhibiting the effects of inflammatory cytokines.

These negative mechanisms of regulating innate responses are not always beneficial. Sometimes, they may possess disadvantages too.

Influenza virus infection causes increased susceptibility to the disease pneumonia by increasing bacterial infections. The RLR signaling pathways triggered by influenza RNA binding activate IRF3, which reduces the transcription of some cytokines induced by TLR signaling. It promotes a protective antibacterial T-cell response.

Effects of excessive innate and inflammatory responses

Innate and inflammatory responses efficiently work to eliminate pathogens and other harmful substances to keep us healthy. They do it without causing any damage to tissues or causing any hindrance to the normal functioning of our body.

But sometimes excess innate and inflammatory responses lead to severe conditions like sepsis, a systemic response to infection. This includes symptoms like fever, elevated heartbeat and heart rate, low blood pressure and limited organ function.

Septicemia is an infection of blood with mainly gram-negative bacteria like Salmonella and E.coli. This leads to sepsis, which can even lead to septic shock, leading to circulatory and respiratory collapse, which has above 90% mortality rate.

Gram-negative bacteria have a cell wall component LPS or endotoxin, which is the major cause of sepsis, an extremely potent inducer of innate immune mediators including TNF-α, IL-1β, and IL-6, chemokines, and antimicrobial components.

To release these soluble mediators, pattern recognition receptors (PRRs) on blood cells like monocytes and neutrophils, vascular endothelial cells, and resident macrophages and cells in the spleen, liver, and other tissues get activated by systemic infections.

Effects of activation of vascular endothelial cells

Vascular endothelial cells then get activated and induced to produce cytokines, chemokines, clotting factors, and adhesion molecules, which increase the inflammatory response. Activated neutrophils and some other cells release enzymes, and reactive oxygen species cause damage to the vasculature.

Tissues get deprived of fluid due to this damage, along with vasodilation and elevated vascular permeability, leading to low blood pressure. Vascular endothelial cells release clotting factors stimulated by TNF, which locally limits the spread of infections but systematically results in blood clotting in capillaries.

Kidneys and lungs are damaged specifically by these effects on the blood vessels. The heart is also adversely affected by the high circulating TNF-α and IL-1 levels. Thus, the condition of septicemia triggers the systemic inflammatory response. This response ultimately leads to the failure of the circulatory and respiratory systems, resulting in septic shock and death.

High levels of TNF-α and IL-1β result in morbidity. During early sepsis, neutralization of these cytokines may be beneficial but after 24 hours from the onset of sepsis, other cytokines like IL-6 and chemokines become more important.

Other than septic shock, there are adverse consequences from chronic inflammatory responses, which can affect our health. The bacterium Helicobacter pylori releases a toxin that damages the stomach by disrupting the links between gastric epithelial cells. It induces chronic inflammation, leading to peptic ulcers and cancer of the stomach.

Pathogens have developed range of strategies to escape innate immune responses

Pathogens have evolved mechanisms through which they can escape the immune responses by prohibiting several innate and inflammatory signaling pathways. Innate immune effector mechanisms can not eliminate microbes due to their high rate of replication.

Complex mechanisms are evolved by other pathogens that do not allow normally effective innate clearance mechanisms. Viruses from their hosts acquire genes that function as inhibitors of innate and inflammatory responses.

Conclusion

Innate immune responses play a vital role in eliminating infections. However, the responses must be regulated in a controlled manner, otherwise, it has adverse effects and can lead to death. There are positive and negative regulatory mechanisms controlling the innate and inflammatory responses.

Excess innate and inflammatory responses lead to severe conditions like sepsis, a systemic response to infection. It includes symptoms like fever, elevated heartbeat and heart rate, low blood pressure, and limited organ function.

Pathogens elude immune responses by prohibiting several innate and inflammatory signaling pathways.