{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCLEC5A—also known as myeloid DAP12‐associating lectin‐1 (MDL‑1)—functions as a key immunomodulatory receptor that couples with signaling adaptors such as DAP10 and DAP12 to regulate immune cell activation across diverse hematopoietic lineages. These adaptor complexes enable cells (including macrophages, dendritic cells, neutrophils, and osteoclast precursors) to detect both endogenous and pathogen‐derived ligands, thereby initiating intracellular cascades that can either trigger or temper inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEngagement of CLEC5A by various viral pathogens—including dengue virus, Japanese encephalitis virus, and influenza virus—leads to DAP12 phosphorylation and the induction of potent proinflammatory signaling. This activation drives the release of cytokines and chemokines that contribute to neuroinflammation, blood–brain barrier disintegration, and even shock in preclinical models, underscoring its pivotal role in virus‐induced immunopathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of skeletal homeostasis and joint inflammation, CLEC5A also plays an important role by promoting osteoclastogenesis and bone erosion. The formation of MDL‑1–DAP12/DAP10 complexes in osteoclast precursors enhances recruitment of inflammatory myeloid cells and accelerates bone resorptive processes during autoimmune joint inflammation, thereby representing a promising target for mitigating immune‐mediated bone pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond viral and skeletal disorders, triggering of CLEC5A on myeloid cells amplifies systemic inflammatory responses by inducing the production of nitric oxide and tumor necrosis factor–α via a signaling network that involves Syk, PI3K, and Akt. Such responses have been implicated in the pathogenesis of conditions ranging from systemic inflammatory response syndrome to chronic obstructive pulmonary disease, with studies showing that alteration or blockade of CLEC5A activity can reduce inflammatory cell infiltration, cytokine secretion, and tissue injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional research has linked CLEC5A to diverse pathological settings. For example, its activation modulates inflammasome assembly and pyroptotic cell death during myocardial infarction, influences macrophage polarization in early atherosclerosis, and even contributes to neuroinflammatory and microglial responses observed in Alzheimer’s disease. Similarly, CLEC5A engagement has been associated with testicular inflammatory responses in Zika virus infection as well as with diabetic peripheral neuropathy through pathways involving endoplasmic reticulum stress and oxidative imbalance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, the compiled evidence reveals that CLEC5A serves as a versatile sensor and mediator of innate immune responses, bridging pathogen recognition with inflammatory and tissue remodeling pathways in both acute infections and chronic inflammatory disorders. Its central role in modulating cytokine release, cell recruitment, and effector functions underlines its potential as a therapeutic target to ameliorate diverse inflammatory pathologies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lewis L Lanier "}, {"type": "b", "children": [{"type": "t", "text": "DAP10- and DAP12-associated receptors in innate immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunol Rev (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-065X.2008.00720.x"}], "href": "https://doi.org/10.1111/j.1600-065X.2008.00720.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19120482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19120482"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Barbara Joyce-Shaikh, Michael E Bigler, Cheng-Chi Chao, et al. 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