The indispensability of macrophage adaptor proteins in chronic inflammatory diseases

Atre, Rajat; Sharma, Rahul; Vadim, Gaponenko; Solanki, Kundan; Wadhonkar, Khandu; Singh, Neha; Patidar, Pramod; Khabiya, Rakhi; Samaur, Harshita; Banerjee, Sreeparna; Baig, Mirza S.

doi:10.1016/j.intimp.2023.110176

Cited by 5 publications

(3 citation statements)

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“…The modular structure of adaptor proteins, which includes one or more specific domains that enable their interaction with various other proteins, is a characteristic feature shared by all adaptor proteins ( 17 ). Adaptor molecules play a key role in the core of various receptor-mediated signaling pathways and act as important mediators bridging the gap between receptors and other molecular components ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look

Baig,

Barmpoutsi,

Bharti

et al. 2024

Front. Immunol.

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Macrophages play a central role in initiating, maintaining, and terminating inflammation. For that, macrophages respond to various external stimuli in changing environments through signaling pathways that are tightly regulated and interconnected. This process involves, among others, autoregulatory loops that activate and deactivate macrophages through various cytokines, stimulants, and other chemical mediators. Adaptor proteins play an indispensable role in facilitating various inflammatory signals. These proteins are dynamic and flexible modulators of immune cell signaling and act as molecular bridges between cell surface receptors and intracellular effector molecules. They are involved in regulating physiological inflammation and also contribute significantly to the development of chronic inflammatory processes. This is at least partly due to their involvement in the activation and deactivation of macrophages, leading to changes in the macrophages’ activation/phenotype. This review provides a comprehensive overview of the 20 adaptor molecules and proteins that act as negative regulators of inflammation in macrophages and effectively suppress inflammatory signaling pathways. We emphasize the functional role of adaptors in signal transduction in macrophages and their influence on the phenotypic transition of macrophages from pro-inflammatory M1-like states to anti-inflammatory M2-like phenotypes. This endeavor mainly aims at highlighting and orchestrating the intricate dynamics of adaptor molecules by elucidating the associated key roles along with respective domains and opening avenues for therapeutic and investigative purposes in clinical practice.

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Section: Introductionmentioning

confidence: 99%

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look

Baig,

Barmpoutsi,

Bharti

et al. 2024

Front. Immunol.

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“…The identification of possible therapeutic targets implicated in the regulation of inflammation offers the opportunity to limit the dangers associated with an imbalance in the inflammatory response (2). Adaptor proteins represent key signaling molecules that regulate the host's innate immune response to infections, acting as links between receptors and other molecules in several signaling cascades (3,4). The evident importance of these proteins in the pathophysiology of different chronic inflammatory illnesses makes them attractive therapeutic targets (4).Here, we focus on a crucial inflammation-related adaptor of Toll-like receptors (TLR), called MyD88 adaptor-like (MAL) or Toll-interleukin-1 Receptor (TIR) domaincontaining adaptor protein (TIRAP).…”

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confidence: 99%

“…Adaptor proteins represent key signaling molecules that regulate the host’s innate immune response to infections, acting as links between receptors and other molecules in several signaling cascades ( 3 , 4 ). The evident importance of these proteins in the pathophysiology of different chronic inflammatory illnesses makes them attractive therapeutic targets ( 4 ).…”

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confidence: 99%

Editorial: Targeting signalling pathways in inflammatory diseases

Baig,

Thurston,

Sharma

et al. 2023

Front. Immunol.

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Editorial on the Research TopicTargeting signalling pathways in inflammatory diseases Chronic inflammation, characterized by a persistent elevation of circulating proinflammatory cytokines, is associated with the pathogenesis of many non-communicable diseases that cause a worldwide health burden and a reduction in quality of life (1). The identification of possible therapeutic targets implicated in the regulation of inflammation offers the opportunity to limit the dangers associated with an imbalance in the inflammatory response (2). Adaptor proteins represent key signaling molecules that regulate the host's innate immune response to infections, acting as links between receptors and other molecules in several signaling cascades (3,4). The evident importance of these proteins in the pathophysiology of different chronic inflammatory illnesses makes them attractive therapeutic targets (4).Here, we focus on a crucial inflammation-related adaptor of Toll-like receptors (TLR), called MyD88 adaptor-like (MAL) or Toll-interleukin-1 Receptor (TIR) domaincontaining adaptor protein (TIRAP). MAL contains a TIR domain, required for mediating interactions with receptors on the membrane and with downstream signaling molecules (5). MAL represents a key mediator of TLR signaling in immune cells such as macrophages (6, 7), where activation of TLR2 and TLR4 cause persistent inflammation in a MAL-dependent fashion (7). Following receptor-mediated detection of pathogenic ligands, MAL mediates various protein-protein interactions (Figure 1A).Tyrosine kinases, including BTK and PKCd, have a major role in the activation of MAL, with BTK mediating phosphorylation on the four MAL residues Y86, Y106, Y159, and Y187 (5), as well as PKCd phosphorylating Y86 and Y106 in MAL's TIR domain (8). The overlapping phosphorylation sites highlight the possible interconnected activities of these kinases with MAL, as well as pointing to possible context-dependent fine-tuning of MAL activity (8). After activation, MAL interacts with critical inflammatory proteins and eventually activates several transcriptional factors involved in the release of proinflammatory cytokines, which consequently leads to an inflammatory response (5). Contrary to phosphorylation, nitric oxide (NO)-mediated S-nitrosylation of Frontiers in Immunology frontiersin.org 01

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