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

Abstract

Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

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

“…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.…”

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

“…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.…”

“…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.…”

“…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.…”

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

“…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).…”