Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

Mackel, Joseph J; Garth, Jaleesa M.; Jones, MaryJane; Ellis, Diandra A; Blackburn, Jonathan P.; Yu, Zhihong; Matalon, Sadis; Curtiss, Miranda L.; Lund, Frances E.; Hastie, Annette T.; Meyers, Deborah A.; Steele, Chad

doi:10.1152/ajplung.00528.2020

Cited by 9 publications

(14 citation statements)

References 70 publications

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“…Examples of the former include studies from our laboratory and others that demonstrated that CHI3L1 inhibits hyperoxia-induced acute lung injury (41,74,75), is a JCI Insight 2021;6(21):e148749 https://doi.org/10.1172/jci.insight.148749 powerful inhibitor of cellular apoptosis (39), and controls bacterial infection via the regulation of inflammasome activation (76). Our studies demonstrated that CHI3L1 is a potent stimulator of type 2 inflammation, M2 macrophage differentiation, and tissue remodeling and that CHI3L1 excess is a major contributor to these responses in allergic and fibrotic disorders (39,67,77,78). The present studies highlight the importance of CHI3L1 as a stimulator of ACE2 and SPP and demonstrate that these inductive events enhance tissue inflammation and injury in COVID-19.…”

Section: Discussionsupporting

confidence: 63%

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19

Kamle¹,

Ma²,

He³

et al. 2021

JCI Insight

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COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.

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Section: Discussionsupporting

confidence: 63%

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19

Kamle¹,

Ma²,

He³

et al. 2021

JCI Insight

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“…Our laboratory focuses on immunopathogenic versus immunoprotective mechanisms during fungal-associated allergic airway inflammation (fungal asthma). Regarding the latter, we have identified CX3CL1/fractalkine as an immunoprotective mediator during fungal asthma ( 41 ) as well as the chitinase-like protein BRP-39 (YKL-40 in humans), although BRP-39 protected the lung during fungal asthma in a yet to be defined nonimmune manner ( 19 ). In contrast, we have identified IL-7 ( 18 ) and IL-1R signaling ( 17 ) as immunopathogenic factors during fungal asthma.…”

Section: Discussionmentioning

confidence: 99%

“…Lung cells were isolated via bronchoalveolar lavage (BAL) as previously described ( 19 ). Cells were washed, and Fc receptors were blocked with Mouse BD Fc Block (BD Biosciences) at 4°C for 20 min.…”

Section: Methodsmentioning

confidence: 99%

“…WT and Alox15 −/− reciprocal chimeric mice were generated by irradiating the indicated recipient mice with 950 Rads from a gamma source (Cesium-137) delivered in one dose ( 19 , 21 ). Following irradiation, mice were intravenously injected with 5 million total bone marrow cells (100% from either WT or Alox15 −/− mice) and were allowed to reconstitute for 8 wk before being subjected to experimental fungal asthma.…”

Section: Methodsmentioning

confidence: 99%

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Hematopoietic 12/15-lipoxygenase activity negatively contributes to fungal-associated allergic asthma

Makullah,

Ellis,

Jones

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

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Asthma is one of the most common non-communicable diseases in the world. Approximately 30% of severe cases are associated with fungal sensitization, often associated with allergy to the opportunistic mold Aspergillus fumigatus. Leukotrienes, immunopathogenic mediators derived from the metabolism of arachidonic acid (AA) by 5-lipoxygenase (5-LOX), are often elevated in severe asthma. As such, these mediators are FDA-approved therapeutic targets of the anti-asthmatic drugs Zileuton®/Zyflo® and Singulair®/Montelukast®. A second enzyme involved in AA metabolism is 12/15-lipoxygenase (12/15-LOX; Alox15). Here, C57BL/6 wild-type mice subjected to experimental fungal asthma had increased expression of Alox15 mRNA as well as increased levels of 12-HETE, a product of 12/15-LOX activity, in the lung when compared to naïve and vehicle-treated mice. Mice deficient in 12/15-LOX ( Alox15-/-) demonstrated better lung function, as measured by airway hyperresponsiveness (AHR), during fungal asthma. Histological assessment revealed reduced inflammation in the lungs of Alox15-/- mice compared to WT mice, which was corroborated by flow cytometric analysis of multiple myeloid (eosinophils, neutrophils) and lymphoid (CD4+ T, γδ T) cell populations. This was further supported by decreased levels of specific chemokines that promote the recruitment of these cells. Likewise, type 1 and 2, but not type 17 cytokines, were significantly lower in the lungs of Alox15-/- mice. Bone marrow chimera studies revealed that the presence of 12/15-LOX in hematopoietic cells contributed to AHR during fungal asthma. Taken together, our data supports the hypothesis that hematopoietic-associated 12/15-LOX contributes to type 2 responses and exacerbation of allergic fungal asthma.

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“…Interestingly, we found that the ECs expressed certain chemotaxis-associated genes, such as Cxcl12, which may further facilitate leukemia cell migration and proliferation. 30 Furthermore, the expression of inflammation-and leukemogenesis-related genes, such as Chil1, [31][32][33] Atf3, 34 and Itgb2, 35 was upregulated in quiescent leukemia cells after chemotherapy (Fig. 4D).…”

Section: Transcriptomic Characteristics Of Ecs and Resting Leukemia C...mentioning

confidence: 96%

Role of the bone marrow vascular niche in chemotherapy for MLL-AF9-induced acute myeloid leukemia

et al. 2023

Blood Science

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Leukemia stem cells in acute myeloid leukemia (AML) can persist within unique bone marrow niches similar to those of healthy hematopoietic stem cells and resist chemotherapy. In the context of AML, endothelial cells (ECs) are crucial components of these niches that appear to promote malignant expansion despite treatment. To better understand these interactions, we developed a real-time cell cycle-tracking mouse model of AML (Fucci-MA9) with an aim of unraveling why quiescent leukemia cells are more resistant to chemotherapy than cycling cells and proliferate during disease relapse. We found that quiescent leukemia cells were more prone to escape chemotherapy than cycling cells, leading to relapse and proliferation. Importantly, post-chemotherapy resting leukemia cells tended to localize closer to blood vessels. Mechanistically, after chemotherapy, resting leukemia cells interacted with ECs, promoting their adhesion and anti-apoptotic capacity. Further, expression analysis of ECs and leukemia cells during AML, after chemotherapy, and after relapse revealed the potential of suppressing the post-chemotherapy inflammatory response to regulate the functions of leukemia cells and ECs. These findings highlight the role of leukemia cells in evading chemotherapy by seeking refuge near blood vessels and provide important insights and directions for future AML research and treatment.

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Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

Cited by 9 publications

References 70 publications

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19

Hematopoietic 12/15-lipoxygenase activity negatively contributes to fungal-associated allergic asthma

Role of the bone marrow vascular niche in chemotherapy for MLL-AF9-induced acute myeloid leukemia

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