The Function of IL-33 as an Alarmin Cytokine

A growing body conclusively demonstrates that the inflammatory reaction of the brain can be encouraged by Aβ plaques. The oligomeric form of the Aβ plaques applies synaptotoxicity. Recently it was also discovered that the Aβ plaque could initiate the cerebral amyloid angiopathy, which initiates the brain hemorrhages and the vascular inflammation. Researches show that the inflammatory processes such as dystrophic microglia, microgliosis, acute phase protein change, cytokine elevation, astrocytosis and complement activation can cause the accumulation of the Aβ plaques in parenchyma and vasculature partially. The ageing and the compromised immune system in elders can lead to the synthesis of the AD. The formation of the AD as a result of allergic inflammation due to parasitic infection or any other reaction and act as an alarming system to alert any immunity compromise in the brain. Recent researches are aiming towards the application of the usefulness of this phenomenon. The following paragraphs will explain the features of the Aβ- reactive CD4 T cells in the mammalian and other animal models and Aβ-based immunotherapeutic methodologies for AD in situation to disease pathogenesis and immunosenescence (Dembic 2015).

This review is to high point the vital role of IL-33, and it’s mode of action as an alarmin. IL-33 fit in to the IL-1 family, and it is a nuclear cytokine mainly influences the epithelial barrier tissue and lymphoid organs. It activates Myd-88 signalling pathways in the target cell showing the ST2/IL-IRAcP receptor complex. The IL-33 plays a crucial role in the expression of the type-2 immunity. Studies show that IL-33 induces allergic reactions as it produces IL-13 and IL-5 with the help of group 2 ILC2s cells like NK cells and mast cells, in the presence of microbial infection. It acts as an alarm signal to alert cell (Arseniy,  Yuzhalin, and Kutikhin, 2015)

Il-33 is a nuclear cytokine which in the beginning selected as NF-HEV. Which have similar structure with IL-1. Interleukin-33 frequently detected as a nuclear protein. Past three years studies indicate that ILC2 secrets enormous amount of IL-13 and IL-5 in response to the IL-33. In major researches in vivo It was found that These interleukin protein plays essential role in the eosinophis homeostatis , type- 2 immunity and allergic inflammations.

The neuropathology of the AD can be identified by the presence of neurofibrillary tangles (NFTs) and abundant amyloid plaque (AP). This results in hyperphosphorylated tau which leads to the loss of neurons. The plaques contain activated microglia surrounded by the reactive astrocytes. On the course of excess pathophysiological events, the IL-33 induces pro-inflammatory reactions and act as the mediator of inflammation of the neurons in CNS. IL-33 activates the inflammatory cells like glial cells. Various cytokines such as TNFα and IL-1β act as the indicator in the AD patients. The IL-33 after cleavage with ST2 act as a mature cytokine. Recent researches showed that IL-33 might heal the central nervous system and other nervous system diseases (Xiong et al. 2014). This cytokine can be genetically linked with the human AD. Some researches showed positive results in the mouse AD models upon injecting the IL-33. IL-33 showed a wide range of expression area in the tissues of the brain (Carlock et al. 2017).

The Role of IL-16 in Inflammatory, Autoimmune, and Degenerative Lesions

Interleukin-16 can be found in the nucleus and cytoplasm as a larger precursor. It act as the regulatory protein of a number of cellular processes. It also act as a protein which includes cell recruitment and cell activation. The synthesis can be done by the cleavage of the C-terminal 14-kDa end. The location of the gene encoding this Interleukin is on chromosome 15q26. IL-16 effectively formed by mast cells, macrophages, CD4⁺T, CD8⁺T, macrophages, eosinophils, epidermal cells and epithelial cells. IL-16 can also be known as the lymphocyte chemo attractant factor (LCF). It act as a transcriptional repressor, which can affect the regulatory effect on cell cycle progression. It is a pro-inflammatory cell mainly produces by the microglia and other variety of cells. Pro-IL-16, the C-terminal domain is primarily secreted by the cells as a ligand for CD4+. The mature IL-16 of the C-terminal domain which is mainly secreted as a ligand from the cells for the CD4 with chemo attractant differentiation factor capabilities and the growth factor on a diversity of  haemapoitic cell types which are mainly intricate in an inflammatory reaction. It includes the differentiate capabilities factor and the growth factor. In addition, it act like a variety of hematopoietic cells involved in the inflammatory response. Microglia act as the first line of cellular defence for any CNS (Central nervous system) disease. Microglia gives inflammatory reactions to many pathological stimuli such as the neurodegeneration, brain injury with inflammation and brain tumours. Microglial activation can be generated by the transitions of the cells into the quiescent stellate form to a macrophage. Then it gradually up regulates the surface antigen and forms a cluster (Guo et al. 2004).

IL-16 mainly act as a first line of defence for the cerebral infection, which can occur due to infection of the foreign cell invasion. It contributes in the cerebral defence mechanism. The mechanism processes through the inflammatory reaction given at the place of neuron damage, brain injury and also in case of the brain tumours. The inflammatory reaction alerts the neighbouring cells and also the immune cells to take proper action towards the incident. The Study suggests IL-16 can suppress the transcription factors of an invasive cell and thus provides a cell cycle arrest for any foreign invasive cell. This results into the Termination of the cells that can raise allergic inflammation in the brain.

Recent data shows that the IL-16  ac n act as the modulator of immunity cytokines that contribute in the regulatory process of the CD4+ cell activation and recruitment at the positions of inflammation which can be caused by the Several autoimmune diseases, sometimes by asthma. The study shows that the IL-16 can act independently without the expression of the CD4+ cells. However, it is also seen that IL-16 cannot induce any migratory signal without the help of CD4+. Researches showed that the population of IL-16 microglia profoundly expresses the presence of IL-16 in the human brain. IL-16 seems to attract CD4+ in the blood-brain barrier under some pathological situation. Center and Cruikshank identified this phenomenon in 1982. In lymphocytes, Study showed that the main receptor for the IL-16 is CD4+, which mainly conveyed on the neuron cells and haemapoitic cells. However, some researches also showed that the CD9 could also induce differentiation and migratory signal in the mast cells like the IL-16.

The Role of CD4 in the Mechanical Properties of the Live Cell Membrane

CD4: The role of CD4 on mechanical properties of the live cell membrane

CD4, which is a 55kDa glycoprotein, is one of the most important membrane protein. Mainly it supports the T cell receptor (TCR) with interacting with the antigen. Major histocompatibility complex class II helps the CD4 for signalling the TCR for binding with the antigen. The interaction among the CD4’s cytoplasmic tails and the lymphocyte-specific protein tyrosinase stabilizes the communication among the TCR and the antigen. This lead to the differentiation and specification of the T cells (Bui and Nguyen 2016). Many functions of the CD4 is thoroughly understood through many investigation and researches and still there are some investigations are going on about the preliminary functions of the in the cell membrane. However, the mechanical function of the CD4 cells are not confirmed through any of these experiments. In addition, whatever information we are getting through these type of experiments is unable to describe all the functionalities of the CD4 cells. All Experiments given to describe the mechanical characteristics of cell membrane is not understood perfectly.

CD 4 cells activates the T cells in order to provide a balancing mechanism in the body that the T cells cannot prevent the self-immune cells. It act as a perfect communication for the T cell to become more stabilize act on the specific designated cells. It also helps in the differentiation of the T cells in to specific order. It is known that the T cells have many varieties; There is T helper cells and cytokines. CD 4 confirms the differentiation in a proper manner.

CD4 ⁺ Foxp3 ⁺ CD25 ⁺ regulatory T cells (Tregs) are the key factors that help in the critical role of maintaining the autoimmunity and in suppressing the excessive immune response to the harmful result of the host. Tregs is suggested to be the crucial factor in the neurodegenerative disease like Parkinson’s disease and amyotrophic lateral sclerosis. It mainly helps in the pathophysiology factors of these neurodegerative desease. However, for Alzheimer disease, the role of Treg is poorly understood. There are many debates on the report of treg impact on Alzheimer disease. Studies suggested that elevation of the suppressive activity in the patient as compare to non-demented control. However, overall lessening frequency of CD4+ CD25 t cells and changed native/memory proportion inside a population were elaborated in the patient with slight Alzheimer disease in compare to age-matched control. It can be determined that overall decrease in the amount of these essential factors can lead to the neuro related disease.

References:

Bui, V.C. and Nguyen, T.H., 2016. The role of CD 4 on mechanical properties of live cell membrane. Journal of Biomedical Materials Research Part A, 104(1), pp.239-244.

Tschammer, N., 2015. Interleukins in Cancer Biology: Their Heterogeneous Role. By Arseniy E. Yuzhalin, Anton G. Kutikhin. ChemMedChem, 10(8), pp.1442-1442.

Dembic, Z., 2015. The Cytokines of the Immune System: The Role of Cytokines in Disease Related to Immune Response. Academic Press.

Guo, L.H., Mittelbronn, M., Brabeck, C., Mueller, C.A. and Schluesener, H.J., 2004. Expression of interleukin-16 by microglial cells in inflammatory, autoimmune, and degenerative lesions of the rat brain. Journal of Neuroimmunology, 146(1-2), pp.39-45.

Xiong, Z., Thangavel, R., Kempuraj, D., Yang, E., Zaheer, S. and Zaheer, A., 2014. Alzheimer’s disease: evidence for the expression of interleukin-33 and its receptor ST2 in the brain. Journal of Alzheimer’s Disease, 40(2), pp.297-308.

Carlock, C., Wu, J., Shim, J., Moreno-Gonzalez, I., Pitcher, M.R., Hicks, J., Suzuki, A., Iwata, J., Quevado, J. and Lou, Y., 2017. Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice. Translational Psychiatry, 7(7), p.e1164.