Convalescent Plasma and Antibody Therapy in COVID-19
Debmalya Barh, Kenneth Lundstrom in COVID-19, 2022
IFNs (IFN-I, IFN-α/β) provide a form of natural antiviral protection during the early stages of viral infection. In the later stages of the disease, the number of proinflammatory interleukins (IL-1 β, IL-6), TNF-α, and C-C motif chemokine ligands (CCL-2, CCL-3, and CCL-5) increase while IFNs decrease. Along with the decreased secretion of IFN, antiviral responses are also hampered by the reduced IFN secretion, which in return is accompanied by a rise in chemokine release attracting a large number of inflammatory cells, such as monocytes and neutrophils. This will result in an excessive inflammatory response. Mononuclear macrophages are activated by the delayed release of IFN-α/β via receptors on their surfaces. CCL2, CCL7, and CCL12, which are monocyte chemoattractants, are released by activated mononuclear macrophages, causing an increase in the number of mononuclear macrophages, which leads to increased levels of proinflammatory cytokines (IL1-, IL-6, and TNF-α) [5].
Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
Genomic instability and uncontrolled proliferative signaling is more relevant to the initiation of tumorigenesis but a majority of cancer-associated deaths are due to metastases of tumor cells [31]. Tumor cells undergo cellular transition i.e. epithelial to mesenchymal transition (EMT), and this process is considered critical for the tumor cells to migrate from primary sites to other (metastatic) sites in the body. Inflammatory cytokines such as IL-6, TNF and IL-1 induce EMT by activating NF-κB and STAT3 signaling [36–38]. IL-4-activated tumor associated macrophages (TAMs) as well as CCR1+ immature myeloid cells secrete matrix degrading enzymes which help in tumor cell invasion [39, 40]. Moreover, CCL-2 mediated recruitment of Gi1+ and CCR2+ inflammatory monocytes helps in the metastases of breast cancer cells and inhibition of CCL2-CCR2 signaling axis increases survival of tumor bearing mice [41]. Thus, prolonged inflammation helps in the cellular transformation and early events of tumorigenesis, whereas inflammatory tumor microenvironment induces tumor aggressiveness in the later events.
Intestinal macrophages in defense of the mucosa
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
In studies of macrophage accumulation in inflamed gastrointestinal mucosa, immunohistochemical analysis has shown that the endothelial cells lining small blood vessels in the mucosa of patients with Crohn's disease display high levels of CD34, a ligand that promotes the rolling of L-selectin+ monocytes in high endothelial venules. More recently, antibody blocking studies have revealed that P-selectin glycoprotein ligand-1, P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) promote CD14+ monocyte rolling and adherence in the intestinal mucosa, particularly ileal mucosa, in a mouse model of spontaneous ileitis. Increased levels of intercellular adhesion molecule-1 (ICAM-1) and CD31, which facilitate the transendothelial migration of monocytes, are also present in Crohn's disease lesions. Thus, endothelial cells in mucosal vessels express molecules that promote the rolling, adherence, and subsequent transendothelial migration of circulating blood monocytes into inflamed gastrointestinal mucosa. In addition, recruitment factors, including CCL2 and CCL4, which selectively induce monocyte transendothelial migration and accumulation, may be released in inflamed and/or infected mucosa, enhancing the migration of monocytes into the mucosa. The interdiction of such recruitment is an attractive therapeutic strategy, but localization of such therapy to inflammatory sites will be difficult to achieve.
A patent review of glutaminyl cyclase inhibitors (2004–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Judite R.M. Coimbra, Jorge A.R. Salvador
CCL2 is a member of the C-C chemokine family and one of the key chemotactic cytokines that regulate migration and infiltration of monocytes with a pivotal role in inflammatory conditions. All members of the CCL2-subfamily are N-terminally modified by a pE-residue and this post-translational modification is fundamental for their bioactivity in vivo, contributing to an efficient receptor interaction and stabilization toward N-terminal proteolytic degradation. Role of the QC activity in CCL2 maturation has been investigated, and isoQC was indicated as the predominant enzyme for this process in vivo [7]. Experimental studies have shown that the inhibition of QC activity significantly reduced the chemoattractant activity of non-modified forms of chemokines and related immune response under inflammatory conditions [7,27]. Moreover, the use of QC/isoQC inhibitors has been shown to modulate the CCL2-mediated liver inflammation in nonalcoholic fatty liver disease in mice [52], and to suppress the progression of inflammation-induced renal dysfunction by hindering the CCL2/CCR2 axis (CCL2 binds primarily to receptor CCR2) [53]. Furthermore, the chemokine domain of CX3CL1 was identified as an additional QC substrate. pE-CX3CL1 binds to the CX3CR1 (fractalkine receptor 1) expressed on the cell surface and activates a signaling process that mediates both adhesion and cell migration in inflammatory processes [11]. The QC-catalyzed N-terminal pE-modification was shown to be required for effective activation of the CX3CL1/CX3CR1 axis.
RelB regulates basal and proinflammatory induction of conjunctival CCL2
Published in Ocular Immunology and Inflammation, 2021
Li-Fong Seet, Li Zhen Toh, Stephanie W. L Chu, Tina T. Wong
CCL2 plays an important role in inflammation by mediating chemotactic macrophage recruitment and polarization at inflammatory sites.38 CCL2 is highly induced in a variety of diseases that feature monocyte-rich cellular infiltrates, including atherosclerosis, congestive heart failure, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis and uveitis, where it is likely to contribute to disease pathogenesis.39 Hence, inflammatory cell infiltrates in the operated conjunctiva may be associated with CCL2 induction, which in the mouse conjunctiva, can be raised by up to 30-folds.11 We have also previously found an association between high CCL2 levels in tears and the propensity to scar after GFS.40 Moreover, we have demonstrated that inhibition of CCL2 signaling had a protective effect on bleb survival in the mouse model of conjunctival scarring.41 Others have demonstrated direct effects of CCL2 on angiogenesis, and fibroblast expression of collagen and matrix metalloproteinase.42–44 All these attributes and associations with inflammatory or scarring pathologies implicate CCL2 as a key contributor to adverse wound healing outcome in GFS. This notion is supported by the identification of CCL2 as a therapeutic target in other major diseases where scarring is an endpoint associated with functional loss.45,46
Antibody-based therapies for idiopathic pulmonary fibrosis
Published in Expert Opinion on Biological Therapy, 2020
Giacomo Sgalla, Mariachiara Flore, Matteo Siciliano, Luca Richeldi
Carlumab (CNTO888) is a recombinant monoclonal antibody directed against human CC chemokine ligand 2 (CCL2), also known as monocyte chemotactic protein-1 (MCP-1). CCL2 is implicated in the pathogenesis of several diseases: its role includes recruitment and migration of monocytes, lymphocytes and dendritic cells, fibroblast recruitment to the site of inflammation, angiogenesis, fibroblast, and myofibroblast collagen synthesis contributing to fibrosis. In vivo and in vitro animal and human studies suggested that increased levels of CCL2 are associated with fibrosis (elevated levels of CCL2 have been found in blood and bronchoalveolar lavage of IPF patients), as well the presence of CCL2-hyperresponsive fibroblasts in the same patients [10]. Other mediators such as IL-13 and TGFβ are linked to the CCL2 pathway; studies using murine models of lung fibrosis have shown that these three molecules seem to mediate each other’s profibrotic activity. In pulmonary fibroblasts, CCL2 inhibition results in a reduction of the profibrotic effect of both IL-13 and TGFβ [11].