The matrix metalloproteinases (MMPs), a family of 25 secreted and cell surface-bound neutral proteinases, process a large array of extracellular and cell surface proteins under normal and pathological conditions. MMPs play critical roles in lung organogenesis, but their expression, for the most part, is downregulated after generation of the alveoli. Our knowledge about the resurgence of the MMPs that occurs in most inflammatory diseases of the lung is rapidly expanding. Although not all members of the MMP family are found within the lung tissue, many are upregulated during the acute and chronic phases of these diseases. Furthermore, potential MMP targets in the lung include all structural proteins in the extracellular matrix (ECM), cell adhesion molecules, growth factors, cytokines, and chemokines. However, what is less known is the role of MMP proteolysis in modulating the function of these substrates in vivo. Because of their multiplicity and substantial substrate overlap, MMPs are thought to have redundant functions. However, as we explore in this review, such redundancy most likely evolved as a necessary compensatory mechanism given the critical regulatory importance of MMPs. While inhibition of MMPs has been proposed as a therapeutic option in a variety of inflammatory lung conditions, a complete understanding of the biology of these complex enzymes is needed before we can reasonably consider them as therapeutic targets.

https://www.physiology.org/doi/pdf/10.1152/physrev.00022.2006

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

Of all cells implicated in the pathology of rheumatoid arthritis (RA), neutrophils possess the greatest cytotoxic potential, owing to their ability to release degradative enzymes and reactive oxygen species. Neutrophils also contribute to the cytokine and chemokine cascades that accompany inflammation, and regulate immune responses via cell-cell interactions. Emerging evidence suggests that neutrophils also have a previously unrecognised role in autoimmune diseases: neutrophils can release neutrophil extracellular traps (NETs) containing chromatin associated with granule enzymes, which not only kill extracellular microorganisms but also provide a source of autoantigens. For example, citrullinated proteins that can act as neoepitopes in loss of immune tolerance are generated by peptidylarginine deiminases, which replace arginine with citrulline residues, within neutrophils. Indeed, antibodies to citrullinated proteins can be detected before the onset of symptoms in patients with RA, and are predictive of erosive disease. Neutrophils from patients with RA have an increased tendency to form NETs containing citrullinated proteins, and sera from such patients contain autoantibodies that recognize these proteins. Thus, in addition to their cytotoxic and immunoregulatory role in RA, neutrophils may be a source of the autoantigens that drive the autoimmune processes underlying this disease.

The multifactorial role of neutrophils in rheumatoid arthritis

Cyclophilin A (CyPA) is a ubiquitously distributed protein belonging to the immunophilin family. CyPA has peptidyl prolyl cis-trans isomerase (PPIase) activity, which regulates protein folding and trafficking. Although CyPA was initially believed to function primarily as an intracellular protein, recent studies have revealed that it can be secreted by cells in response to inflammatory stimuli. Current research in animal models and humans has provided compelling evidences supporting the critical function of CyPA in several human diseases. This review discusses recently available data about CyPA in cardiovascular diseases, viral infections, neurodegeneration, cancer, rheumatoid arthritis, sepsis, asthma, periodontitis and aging. It is believed that further elucidations of the role of CyPA will provide a better understanding of the molecular mechanisms underlying these diseases and will help develop novel pharmacological therapies.

/pdf/cyclophilin-a-a-key-player-for-human-disease-2y5rxrhnbi.pdf

Cyclophilin A: A key player for human disease

CD147 immunoglobulin superfamily receptor function and role in pathology

Immunophilins are chaperones that may also exhibit peptidylprolyl isomerase (PPIase) activity This review summarizes our knowledge of the two largest families of immunophilins, namely cyclophilin and FK506-binding protein, and a novel chimeric dual-family immunophilin, named FK506- and cyclosporin-binding protein (FCBP) The larger members of each family are modular in nature, consisting of multiple PPIase and/or protein-protein interaction domains Despite the apparent difference in their sequence and three-dimensional structure, the three families encode similar enzymatic and biological functions Recent studies have revealed that many immunophilins possess a chaperone function independent of PPIase activity Knockout animal studies have confirmed multiple essential roles of immunophilins in physiology and development An immunophilin is indeed a natural ‘protein-philin’ (Greek ‘philin’ = friend) that interacts with proteins to guide their proper folding and assembly

Immunophilins: for the love of proteins.

The main regulators of leukocyte trafficking during inflammatory responses are chemokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Cyclophilins can induce leukocyte chemotaxis in vitro and have been detected at elevated levels in inflamed tissues, suggesting that they might contribute to inflammatory responses. We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury. Blocking cyclophilin-CD147 interactions by targeting CD147 (using anti-CD147 Ab) or cyclophilin (using nonimmunosuppressive cyclosporine A analog) reduced tissue neutrophilia by up to 50%, with a concurrent decrease in tissue pathology. These findings are the first to demonstrate the significant contribution of cyclophilins to inflammatory responses and provide a potentially novel approach for reducing inflammation-mediated diseases.

Extracellular Cyclophilins Contribute to the Regulation of Inflammatory Responses

Extracellular cyclophilins have been well described as chemotactic factors for various leukocyte subsets. This chemotactic capacity is dependent upon interaction of cyclophilins with the cell surface signaling receptor CD147. Elevated levels of extracellular cyclophilins have been documented in several inflammatory diseases. We propose that extracellular cyclophilins, via interaction with CD147, may contribute to the recruitment of leukocytes from the periphery into tissues during inflammatory responses. In this study, we examined whether extracellular cyclophilin-CD147 interactions might influence leukocyte recruitment in the inflammatory disease allergic asthma. Using a mouse model of asthmatic inflammation, we show that 1) extracellular cyclophilins are elevated in the airways of asthmatic mice; 2) mouse eosinophils and CD4 + T cells express CD147, which is up-regulated on CD4 + T cells upon activation; 3) cyclophilins induce CD147-dependent chemotaxis of activated CD4 + T cells in vitro; 4) in vivo treatment with anti-CD147 mAb significantly reduces (by up to 50%) the accumulation of eosinophils and effector/memory CD4 + T lymphocytes, as well as Ag-specific Th2 cytokine secretion, in lung tissues; and 5) anti-CD147 treatment significantly reduces airway epithelial mucin production and bronchial hyperreactivity to methacholine challenge. These findings provide a novel mechanism whereby asthmatic lung inflammation may be reduced by targeting cyclophilin-CD147 interactions.

Novel Approach to Inhibit Asthma-Mediated Lung Inflammation Using Anti-CD147 Intervention

CD147 is a type I transmembrane glycoprotein expressed on a wide variety of cell types, including all leucocytes. While CD147 is best known as a potent inducer of matrix metalloproteinases, it can also function as a regulator of leucocyte migration through its cell surface interaction with chemotactic extracellular cyclophilins. A potential role for CD147-cyclophilin interactions during inflammatory diseases, including rheumatoid arthritis (RA), is suggested from several studies. For example, CD147 expression is increased on reactive leucocytes in the synovial fluid and tissues of patients with arthritis. In addition, the synovial fluid of patients with RA contains high levels of extracellular cyclophilin A. In the current studies we investigated the contribution of the chemotactic function of CD147-cyclophilin interactions to joint inflammation using the mouse model of collagen-induced arthritis. Our data demonstrate that proinflammatory leucocytes, specifically neutrophils, monocytes and activated CD4(+) T cells, lose their ability to migrate in response to cyclophilin A in vitro when treated with anti-CD147 monoclonal antibody. Furthermore, in vivo treatment with anti-CD147 monoclonal antibody can reduce the development of collagen-induced arthritis in mice by >75%. Such findings suggest that CD147-cyclophilin interactions might contribute to the pathogenesis of RA by promoting the recruitment of leucocytes into joint tissues.

Ifeanyi Okwumabua

Papers

Extracellular Cyclophilins Contribute to the Regulation of Inflammatory Responses

Novel Approach to Inhibit Asthma-Mediated Lung Inflammation Using Anti-CD147 Intervention

Targeting the chemotactic function of CD147 reduces collagen-induced arthritis.