Interleukin 1α (IL-1α) Promotes Pathogenic Immature Myeloid Cells and IL-1β Favors Protective Mature Myeloid Cells During Acute Lung Infection

Periasamy, Sivakumar; Harton, Jonathan A.

doi:10.1093/infdis/jiy049

Cited by 13 publications

(6 citation statements)

References 48 publications

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“…IL-1α −/− mice (but not IL-1β −/− mice) challenged with inhaled silicone, an inflammasome (NLRP3) activator,55 develop PAP-like LD 56. In the lung, IL-1 regulates granulocyte-macrophage colony-stimulating factor (GM-CSF) levels57 58 and macrophage function56 57; disruption of either can lead to surfactant accumulation and PAP 59 60. These findings imply a link between reduced IL-1 and PAP, but also suggest that additional triggers may be required for disease development, in line with the rarity of severe parenchymal LD among the overall population of patients with sJIA treated with IL-1/IL-6 inhibitors.…”

Section: Discussionmentioning

confidence: 73%

Emergent high fatality lung disease in systemic juvenile arthritis

et al. 2019

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ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.ConclusionsA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

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Section: Discussionmentioning

confidence: 73%

Emergent high fatality lung disease in systemic juvenile arthritis

et al. 2019

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“…IL-1 α -/- mice (but not IL-1 β -/- mice) challenged with inhaled silicone, an inflammasome (NLRP3) activator,[55] develop PAP-like lung disease. [56] In the lung, IL-1 regulates GM-CSF levels[57,58] and macrophage function;[56,57] disruption of either can lead to surfactant accumulation and PAP. [59,60] These findings imply a link between reduced IL-1 and PAP, but also suggest that additional triggers may be required for disease development, in line with the rarity of severe parenchymal LD among the overall population of sJIA patients treated with inhibitors.…”

Section: Discussionmentioning

confidence: 99%

An emergent, high-fatality lung disease in systemic juvenile arthritis

Saper

Chen

Deutsch

et al. 2019

Preprint

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Objective To investigate characteristics and risk factors of a novel parenchymal lung disease, increasingly detected in systemic juvenile idiopathic arthritis (sJIA). Methods In a multi-center retrospective study, 61 cases were investigated, using physician-reported clinical information and centralized analyses of radiologic, pathologic and genetic data. Results Lung disease (LD) was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the IL-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes +/- ground glass opacities. Predominant pathology (23/36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features, including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. 5-year survival was 42%. Whole-exome sequencing (20/61) did not identify a novel monogenic defect PAP-related or macrophage activation syndrome (MAS)-related mutations as likely primary cause. Trisomy 21 (T21) increased LD risk, as did young sJIA onset. Refractory sJIA was not required for LD development. Exposure to interleukin (IL)-1 and IL-6 inhibitors (46/61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but it was not associated with LD features. Conclusions A rare, life-threatening LD in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

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“…Although the engagement of both TLR2 and TLR3 by schistosome eggs is important for the production of inflammatory cytokines and interferon-stimulated genes, such as some chemokines, by DCs [ 18 ], no significant differences of TLR3 expressions were observed in pDCs, cDCs, neutrophils, and macrophages ( P > 0.05, Figure 4(b) ). It might relate to the fact that myeloid cells mainly play function on the site of local inflammation [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

TLR3 Modulates the Response of NK Cells against Schistosoma japonicum

Xie

et al. 2018

Journal of Immunology Research

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Natural killer (NK) cells are classic innate immune cells that play roles in many types of infectious diseases. NK cells possess many kinds of TLRs that allow them to sense and respond to invading pathogens. Our previous study found that NK cells could modulate the immune response induced by Schistosoma japonicum (S. japonicum) in C57BL/6 mice. In the present study, the role of TLRs in the progress of S. japonicum infection was investigated. Results showed that the expression of TLR3 on NK cells increased significantly after S. japonicum infection by using RT-PCR and FACS (P < 0.05). TLR3 agonist (Poly I:C) increased IFN-γ and IL-4 levels in the supernatant of cultured splenocytes and induced a higher percentage of IFN-γ- and IL-4-secreting NK cells from infected mouse splenocytes (P < 0.05). Not only the percentages of MHC II-, CD69-, and NKG2A/C/E-expressing cells but also the percentages of IL-4-, IL-5-, and IL-17-producing cells in TLR3+ NK cells increased significantly after infection (P < 0.05). Moreover, the expression of NKG2A/C/E, NKG2D, MHC II, and CD69 on the surface of splenic NK cells was changed in S. japonicum-infected TLR3−/− (TLR3 KO mice, P < 0.05); the abilities of NK cells in IL-4, IL-5, and IL-17 secretion were decreased too (P < 0.05). These results indicate that TLR3 is the primary molecule which modulates the activation and function of NK cells during the course of S. japonicum infection in C57BL/6 mice.

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Interleukin 1α (IL-1α) Promotes Pathogenic Immature Myeloid Cells and IL-1β Favors Protective Mature Myeloid Cells During Acute Lung Infection

Cited by 13 publications

References 48 publications

Emergent high fatality lung disease in systemic juvenile arthritis

Emergent high fatality lung disease in systemic juvenile arthritis

An emergent, high-fatality lung disease in systemic juvenile arthritis

TLR3 Modulates the Response of NK Cells against Schistosoma japonicum

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