Abstract
Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors.
Highlights
Macrophages, first described by Russian zoologist Metchnikoff in 1892, are a key player in innate, as well as adaptive, immunity
The RLR family mainly consists of two members, retinoic acid-inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA5), both caspase activation and recruitment domains (CARDs) containing cytosolic pattern recognition receptors (PRRs) found in most cell types
During TLR4-mediated signaling, TRAF3 is regulated by USP25, which is known as an essential endotoxin tolerance (ET) regulator in macrophages as well as functioning in protein degradation associated with ER and in cell migration and invasion [57,84]
Summary
Macrophages, first described by Russian zoologist Metchnikoff in 1892, are a key player in innate, as well as adaptive, immunity. As a part of innate immunity, they conserve phagocytic activity and initiate protective inflammatory responses for the recognition and elimination of microbes like bacteria, fungi, and viruses They exhibit functions associated with T and B cell response as a part of adaptive immunity [5,6]. Recent advances have shown that RLR-mediated signal transduction inducing antiviral immune response is controlled stringently by post-translational modifications (PTMs) including ubiquitination and deubiquitination [12,13]. Another host cell arsenal against infecting microbes is the macrophage inflammatory activation, which is regulated by ubiquitination and deubiquitination; dysregulated ubiquitination leads to several inflammatory diseases. It is important to provide a better understanding regarding the DUBs regulating macrophages for its antiviral and inflammatory response against invading pathogens and certain inhibitors of ubiquitin machinery that have paved the way as an attractive therapeutic approach for aberrant immune response
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