Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure

Abstract

Chitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) () deficiency on host defense during acute exposure to the fungal pathogen as well as its contribution to-associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels in conidia, which emerged at the highest level during hyphal transition. In response to acute challenge, mice unexpectedly demonstrated lower lung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1β and prostaglandin E (PGE) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronic exposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses.

IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation

“…The low-frequency/broadband forced oscillation technique was employed to measure Newtonian resistance (Rn; also known as airway hyperreactivity), tissue damping (G), and tissue elastance (H). All measurements were collected at baseline and after a linear dose response with methacholine challenge (10-40 mg/mL), as previously described (10,16). Lung function was also assessed in naive WT and mutant mice, which confirmed no baseline anomalies and no differences between groups, as we have previously reported (11).…”

“…Regarding Il1rn -/mice, eosinophils were significantly decreased and neutrophils were significantly increased in whole lungs (Figure 6B), which is consistent with the lung lavage fluid data ( Figures 4B and Figure 5B). We have previously reported that IL-17A and IL-22 function in an immunopathogenic manner during experimental fungal-associated allergic airway inflammation (11,16). We recently reported that CD4 + T cells, as well as the innate lymphocytes γδ T cells, and invariant NKT cells (iNKT) cells were cellular sources of IL-22 (and likely IL-17A) in the lung during experimental fungal-associated allergic airway inflammation (10).…”

“…Lung cell flow cytometry. Lung cells were isolated via BAL or by enzymatic digestion of whole lungs as previously described (11,16). Cells were washed, and Fc receptors were blocked with Mouse BD Fc Block (BD Biosciences) at 4°C for 20 minutes.…”

Chitin and Chitosan Derivatives as Biomaterial Resources for Biological and Biomedical Applications

“…Chitotriosidase was also involved in lung diseases such as tuberculosis, chronic obstructive lung diseases [ 80 ]. Apart from chitotriosidase, acute exposure to the fungal pathogen Aspergillus fumigatus promoted the function of acidic mammalian chitinase, which determined the severity of fungal asthma [ 81 ]. Therefore, inhibition of chitotriosidase and acidic mammalian chitinase is regarded as a drug target for respiratory diseases [ 82 ].…”

Targeting Cytokines as Evolving Treatment Strategies in Chronic Inflammatory Airway Diseases

“…ICSs have high efficiency in treating asthma but are only partially effective in controlling airway inflammation. Moreover, ICSs have been linked to adverse cardiovascular effects in COPD patients, growth stunts in pediatric CF bronchiectasis patients, and withdrawal complications [ 75 , 79 , 80 ]. The biggest limitation of these inhaled therapies is their inability to aid in regulating disease modification and/or progression.…”