Macrophage Polarization Is Decisive for Chronic Bacterial Infection-Induced Carcinogenesis

Macrophages are the special cells of the immune system and play both immunological and physiological role. One of the peculiar characteristics of macrophages is that they are double-edged and highly plastic component of immune system. Due to this characteristic, they are responsible for both progressions as well control of a variety of inflammatory, infectious and metabolic diseases and cancer. These are found in the body in three major phenotypes, which are known as M0 (also known as naïve); M1 (classically activated macrophages); and/or M2 (alternatively activated macrophages) at normal physiological conditions. We have been exploring macrophages in context of bacterial infection and previously demonstrated that M2 polarization of M1 effector alveolar macrophages during chronic/persistent Chlamydia pneumonia, Mycobacterium tuberculosis and Helicobacter pylori pathogens are decisive for the infection induced cancer development in host. Since chronic infection with these pathogens has been associated with adenocarcinoma, therefore, we feel that disruption of macrophage plasticity plays crucial role in the host for the development of cancer. On the basis of this, we propose that in such pathological conditions, management of M1/M2 imbalance is paramount for minimizing the risk of developing cancer by chronic and persistent infection

Pathogenic Role of iNOs+ M1 Effector Macrophages in Fibromyalgia

Fibromyalgia (FM) or Fibromyalgia Syndrome (FMS) is a neurodegenerative disorder causing musculoskeletal pain, tenderness, stiffness, fatigue, and sleep disorder in the body. It is one of the most common chronic pain conditions, affecting about 6% of the world population. Being refractory, till date, no specific treatment of this disease is available. Accumulating evidences over the last few decades indicate that proinflammatory macrophages, cytokines, & chemokines as the key players in this disease. Recent findings suggest activation of Microglial cells and associated pro-inflammatory signals as one of the major causes of chronic pain in patients suffering from fibromyalgia. Increased density of iNOs/CD68+ M1 effector macrophages has been associated with neuropathic pain models. In light of this, depletion of these pro-inflammatory macrophages has been shown to reduce sensitivity to neuropathic pain. On the other hand, modulating pattern of AGEs (Advanced Glycation End-Products) can also contribute to inactivation of macrophages. These findings strongly suggest that macrophages are critical in both inflammatory and neuropathic pain. Therefore, this chapter highlights the impact of macrophage plasticity in various immunopathological aspects of fibromyalgia

cIAP-1 Controls Innate Immunity to C. pneumoniae Pulmonary Infection

The resistance of epithelial cells infected with Chlamydophila pneumoniae for apoptosis has been attributed to the induced expression and increased stability of anti-apoptotic proteins called inhibitor of apoptosis proteins (IAPs). The significance of cellular inhibitor of apoptosis protein-1 (cIAP-1) in C. pneumoniae pulmonary infection and innate immune response was investigated in cIAP-1 knockout (KO) mice using a novel non-invasive intra-tracheal infection method. In contrast to wildtype, cIAP-1 knockout mice failed to clear the infection from their lungs. Wildtype mice responded to infection with a strong inflammatory response in the lung. In contrast, the recruitment of macrophages was reduced in cIAP-1 KO mice compared to wildtype mice. The concentration of Interferon gamma (IFN-γ) was increased whereas that of Tumor Necrosis Factor (TNF-α) was reduced in the lungs of infected cIAP-1 KO mice compared to infected wildtype mice. Ex vivo experiments on mouse peritoneal macrophages and splenocytes revealed that cIAP-1 is required for innate immune responses of these cells. Our findings thus suggest a new immunoregulatory role of cIAP-1 in the course of bacterial infection

Sphingolipids Are Dual Specific Drug Targets for the Management of Pulmonary Infections: Perspective

Sphingolipids are the major constituent of the mucus secreted by the cells of epithelial linings of lungs where they maintain the barrier functions and prevent microbial invasion. Sphingolipids are interconvertible, and their primary and secondary metabolites have both structural and functional roles. Out of several sphingolipid metabolites, sphingosine-1 phosphate (S1P) and ceramide are central molecules and decisive for sphingolipid signaling. These are produced by enzymatic activity of sphingosine kinase-1 (SK-1) upon the challenge with either biological or physiological stresses. S1P and ceramide rheostat are important for the progression of various pathologies, which are manifested by inflammatory cascade. S1P is a well-established secondary messenger and associated with various neuronal, metabolic, and inflammatory diseases other than respiratory infections such as Chlamydia pneumoniae, Streptococcus pneumoniae, and Mycobacterium tuberculosis. These pathogens are known to exploit sphingolipid metabolism for their opportunistic survival. Decreased sphingosine kinase activity/S1P content in the lung and peripheral blood of tuberculosis patients clearly indicated a dysregulation of sphingolipid metabolism during infection and suggest that sphingolipid metabolism is important for management of infection by the host. Our previous study has demonstrated that gain of SK-1 activity is important for the maturation of phagolysosomal compartment, innate activation of macrophages, and subsequent control of mycobacterial replication/growth in macrophages. Furthermore, S1P-mediated amelioration of lung pathology and disease severity in TB patients is believed to be mediated by the selective activation or rearrangement of various S1P receptors (S1PR) particularly S1PR2, which has been effective in controlling respiratory fungal pathogens. Therefore, such specificity of S1P–S1PR would be paramount for triggering inflammatory events, subsequent activation, and fostering bactericidal potential in macrophages for the control of TB. In this review, we have discussed and emphasized that sphingolipids may represent effective novel, yet dual specific drug targets for controlling pulmonary infections

Caloric restriction mimetics chlorogenic acid and fisetin as potential autophagy inducers targeting ATG101

Autophagy is an important cytoprotective process impaired in neurodegenerative diseases such as Alzheimer's disease. The initiation process is mediated by the protein kinase Unc-51-like kinase 1 (ULK1) complex. ATG101, a cytosolic protein, plays a pivotal role in initiating autophagy as a component of the ULK complex in mammalian cells. It is important to understand the regulatory processes of individual autophagy components under different conditions for the development of therapeutic interventions. The caloric restriction mimetics (CRMs) such as chlorogenic acid (CGA) and fisetin mimic the healthy outcomes of caloric restriction without decreasing caloric consumption, constituting promising therapeutic candidates for neuroprotection. We explored the ATG101 interactions of CGA and fisetin in this work. Molecular docking and molecular dynamics (MD) simulations were used to investigate the interactions of these CRMs with ATG101, evaluating binding stability and dynamics. To confirm these interactions, we conducted quantitative real-time PCR (qRT-PCR) in differentiated SHSY5Y cells, analyzing the effect of CGA and fisetin on ATG101 gene expression. Our results indicated that fisetin forms a more stable complex with ATG101 compared to CGA. Yet, at the transcriptional level, both CRMs stimulate the mRNA level of ATG101. Therefore, these CRMs can be responsible for their potential as autophagy inducers. These findings offer significant insights into the molecular processes through which CRMs may improve neurodegenerative diseases by triggering autophagy

Interferon and HPA Axis: Impact on Neuroimmunological Perturbations

The interplay between the central nervous system (CNS) and the enteric nervous system (ENS) constitutes the gut-brain axis. This represents a dynamic and bidirectional network of signaling pathways involving the vagus nerve, the immune system, and the molecules released by various microorganisms thriving in our gut. Since humans and bacteria have evolved together and learned to live together in a symbiotic relationship, which is decisive for physio/immune homeostasis of the body. Disruption in this (also known as dysbiosis) is associated with various pathological consequences including several neurological disorders. Out of several pathways that are associated with neurological manifestation, the inflammasome pathway is associated with the progression of multiple sclerosis, Alzheimer’s, and Parkinson’s disease, depression, schizophrenia, and autism. A growing body of evidence now suggests a reciprocal influence of microbiota and inflammasome activation in the brain. In this chapter, we discuss the cross talk between human gut microbiota and the key immunological signaling processes and their role in CNS development and neurological diseases

Employing Mesenchymal Stromal Cells (MSC) for Managing Acute and Chronic Graft-versus-Host-Disease

Mesenchymal Stromal Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune conditioning and regenerative potential which qualify them as potential component of cell based therapy for various autoimmune / chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. In view of this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host Disease (aGVHD), one of the autoimmune manifestation in human.. In pre-clinical models, MSCs have been shown to reduce the severity of aGVHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in aGVHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. In view of these inevitable issues, here we discuss various mechanisms, how MSCs can be employed in managing aGVHD, as a therapeutic option for this disease.</jats:p