OXIDATIVE STRESS IN IMMUNE RESPONSE

OXIDATIVE STRESS IN IMMUNE RESPONSE

Oxidative stress is an imbalance of free radicals and antioxidants in the body, which can lead to cell and tissue damage. Oxidative stress occurs naturally and plays a role in the aging process.

Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by reactive oxygen species (ROS) generated, e.g. O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide) [1]. Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

In humans, oxidative stress is thought to be involved in the development of ADHD, cancer,Parkinson's disease, Lafora disease, Alzheimer's disease, atherosclerosis, heart failure,and  myocardial infarction. Oxidative stress is a normal occurrence during the immune system’s inflammatory response to infection or injury. Inflammation plays a vital role in the body’s response to pathogens and tissue damage. However, considerable evidence now points to oxidative stress from chronic inflammation as a contributing factor in a number of health and production disorders in cattle [2].

OXIDATIVE STRESS AND AGING RELATED DISEASE

Oxidative stress, cellular senescence, and consequently, SASP factors are involved in several acute and chronic pathological processes, such as CVDs, acute and chronic kidney disease (CKD), neurodegenerative diseases (NDs), macular degeneration (MD), biliary diseases, and cancer. Cardiovascular (CV) risk factors (ie, obesity, diabetes, hypertension, and atherosclerosis) are associated with the inflammatory pathway mediated by IL-1α, IL-6, IL-8, and increased cellular senescence [3].

Moreover, vascular calcification is linked to an SASP-driven osteoblastic transdifferentiation of senescent smooth muscle cells. In many neurodegenerative conditions, including Alzheimer’s disease (AD), brain tissue biopsies show increased levels of p16, MMP, and IL-6 [4]. Chronic obstructive pulmonary disease, biliary cirrhosis, cholangitis, and osteoarthritis share several damaging SASP profiles including IL-6, IL-8, and MMP.Diabetes mellitus (type 1 and 2) is a metabolic disease associated with increased formation of free radicals and decreased antioxidant potential, leading to macro- and microvascular complications. The precise mechanism by which oxidative stress may accelerate the development of complications in diabetes is only partly known. Oxidant stress in type 2 diabetes (T2D) promotes prothrombotic reactions, leading to CV complications.

 Macrophage during inflammation and role of oxygen and nitrogen species

Macrophages (ΜΦs) are part of the innate immune system and can differentiate into several subtypes with opposite functions in the course of the immune and inflammatory response. Their activation plays a central role in both innate and acquired immunity, which suggests a tightly regulated switch in response to environmental conditions that promote ΜΦ recruitment via tissue infiltration. The high plasticity of ΜΦs enables these cells to respond and adapt to the specific requirements of the inflamed area. The functions of ΜΦs include host defense against pathogens, phagocytosis and pathogen killing, bone dynamics, antigen presentation, local inflammatory reactions, wound healing, blood lipid homeostasis and tissue remodelling. Reactive oxygen and nitrogen species (ROS and RNS, respectively) are also prototypical ΜΦ mediators that play a central role in effector functions. ΜΦs increase ROS and RNS production after exposure to a number of different signals including pathogen-derived or damage associated molecular patterns (PAMPs, such as lipopolysaccharide or DAMPs, such as high-mobility box 1 protein, nucleotides, and DNA, respectively), cytokines (e.g. TNFα, IFNγ), metabolic stress (e.g. hyperglycemia, advanced glycation endproducts, oxidized lipoproteins), endoplasmic reticulum stress, unfolded protein accumulation (unfolded protein response; UPR), and various nanoparticles. This exacerbated release of ROS and RNS constitutes the oxidative burst: a defense mechanism initiated by ΜΦs to destroy pathogens thanks to the bactericidal activity of ROS and RNS.

 

Fig 1: Mechanisms of reactive oxygen and nitrogen species generation in macrophages

 ROS are generated via enzymatic reactions mediated by NADPH oxidase 2 (NOX2) and xanthine oxidase (XO) and/or as a result of mitochondrial respiratory dysfunction. RNS production is mainly driven by NOS2, whose main product, NO, has either pro- or anti-apoptotic and survival functions, depending on the generation rate. Both ROS and RNS dramatically affect cell metabolism, DNA integrity, and macrophage viability.

 

The most important sources of ROS in activated ΜΦs are NADPH oxidase 2 (NOX2), xanthine oxidase (XO), and the mitochondrial electron transport chain. Superoxide (O₂^●-), and hydrogen peroxide (H₂O₂) generated by these systems play signaling roles, but may also contribute to cell dysfunction and death [5].

 

REFERENCE

[1] Birnboin, H. C. (1986). "DNA strand breaks in human leukocytes induced by super-oxide anion, hydrogen peroxide and tumor promoters are repaired slowly compared to breaks induced by ionizing radiation". Carcinogenesis. 7: 1511–1517. doi:10.1093/carcin/7.9.151.

[2] Julia Hamann, D.V.M.” Oxidative stress: Impact on dairy health and immune function” Published on: 8/10/2015.

[3]  Chandrasekaran A, Idelchik MDPS, Melendez JA. Redox control of senescence and age-related disease. Redox Biol. 2017;11:91–102.

[4] Burton DGA, Matsubara H, Ikeda K. Pathophysiology of vascular calcification: pivotal role of cellular senescence in vascular smooth muscle cells. Exp Gerontol.

[5] László Virág,a, Rafael I. Jaén, Zsolt Regdon, Lisardo Boscá, and Patricia Prieto.” Self-defense of macrophages against oxidative injury: Fighting for their own survival” Redox Biol.2019 Sep; 26: 101261. Published online 2019 Jun 28.doi:10.1016/j.redox.2019.101261.