Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases

Abstract

Toll-like receptors (TLRs), which are found in innate immune cells, are essential mediators of rapid inflammatory responses and appropriate T-cell activation in response to infection and tissue damage. Accumulating evidence suggests that TLR signaling is involved in normal hematopoiesis and specific hematologic pathologies. Particular TLRs and their downstream signaling mediators are expressed not only in terminally differentiated innate immune cells but also in early hematopoietic progenitors. Sterile activation of TLR signaling is required to generate early embryonic hematopoietic progenitor cells. In adult animals, TLR signaling directly or indirectly promotes differentiation of myeloid cells at the expense of that of lymphoid cells and the self-renewal of hematopoietic stem cells during infection and tissue damage. Activating mutations of the MyD88 gene, which codes for a key adaptor involved in TLR signaling, are commonly detected in B-cell lymphomas and other B-cell hematopathologies. Dysregulated TLR signaling contributes to the pathogenesis of many hematopoietic disorders, including bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia. Complete elucidation of the molecular mechanisms by which TLR signaling mediates the regulation of both normal and pathogenic hematopoiesis will prove valuable to the development of targeted therapies and strategies for improved treatment of hematopoietic disorders.

Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure

“…The increased expression of TLRs ( Tlr1 , Tlr9 , and Tlr13 ) and TNF family members along with activated non‐canonical NF‐κB pathway suggested that inflammatory responses were also involved in the observed HSPC defects (Fig. A) . Consistent with the enhanced inflammatory response, Ly6a (Sca1), a direct target of interferon‐γ, was upregulated (Fig.…”

Toll-Like Receptors 2 and 4 Modulate Pulmonary Inflammation and Host Factors Mediated by Outer Membrane Vesicles Derived from Acinetobacter baumannii

“…Both TLR2 and TLR4 are expressed on the cell surface of macrophages and signal via the common adaptor protein MyD88 (11,20). IL-6 is a proinflammatory cytokine secreted by macrophages that leads to the recruitment of neutrophils to the sites of infection (18,20).…”

The Role of Innate Immunity Factors in Tumorigenesis Process

“…Канцерогенез в коже зависит от повышенной экспрессии TLR4 миелоидными и эпителиальными клетками, а также от наличия TLR4 эндогенного лиганда -HMGB1 (high-mobility group protein B1). Факт, что TLR4 оказывает защитную роль в невоспалительной модели канцерогенеза кожи, предполагает, что влияние TLR4 на рак кожи может зависеть от условий микроокружения опухоли [7,51]. В поджелудочной железе ингибирование TLR4 уменьшает рост опухоли, в то время как постоянное воздействие ЛПС ускоряет прогрессирование рака.…”

“…Сотни SNPs (single nucleotide polymorphisms) были идентифицированы в генах TLRs, но связь с функцией не была раскрыта в подавляющем большинстве. Существует множество работ, описывающих ассоциацию полиморфных маркеров в генах TLRs и с инфекционными заболеваниями, и с образованием опухолей [7,39]. К TLR2-подсемейству относятся TLR2, TLR1 и TLR6, которые имеют высокую степень гомологии, следует отметить, что гены TLR1 и TLR6 образуют кластер с геном TLR10 в районе 4p14.…”