Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

Zhou, Yang; He, Chuan; Herzog, Erica L.; Peng, Xueyan; Nguyen, Tung H.; Gulati, Mridu; Gochuico, Bernadette R.; Gahl, William A.; Slade, Martin L.; Lee, Chang-Min; Elias, Jack A.

doi:10.1172/jci79792

Cited by 64 publications

(97 citation statements)

References 66 publications

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“…With aging, spontaneous fibrosis has been reported in an HPS double-mutant model, generated by mating HPS-1 and HPS-2 mice (51). Alveolar epithelial cell dysfunction in HPS remains under study, but publications implicate alveolar epithelial cell apoptosis (51, 52), chitinase-3-like-1 and its receptors (53), and autophagy (54) as potential mechanisms. Macrophage-mediated inflammation is also present in HPS mouse models.…”

Section: Murine Modelsmentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

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Section: Murine Modelsmentioning

confidence: 99%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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“…Although HPS AECs produced only modestly elevated levels of GM-CSF, it is possible that these and other factors in addition to MCP-1 also play a role in macrophage recruitment and activation in HPS. For example, levels of chitinase 3-like 1 (CHI3L1) are increased in the plasma of HPS patients and may also contribute to M2 macrophage polarization and AEC apoptosis (23). In addition to excessive TGF-β production, we recognize that there are other potential mechanisms by which HPS macrophages could contribute to lung fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Young¹,

Gulleman²,

Short³

et al. 2016

JCI Insight

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“…Our investigations revealed that Chil1 signals through an IL-13R␣2-dependent and an IL-13R␣2-independent mechanism. The IL-13R␣2-independent signaling mechanism remains elusive, but it may involve the pro-Th2 receptor CRTH2 or another, unidentified pathway (25).…”

Section: Discussionmentioning

confidence: 99%

“…Chil1 is a secreted protein and is known to be expressed by both bone marrow-derived macrophages (BMDMs) and stromal cells (20,21). The protein is also expressed in healthy volunteers into whom Escherichia coli endotoxin is injected; in the sera of patients with pneumococcal pneumonia; and in patients with COPD, asthma, cancer, arthritis, and lung fibrosis (20,(22)(23)(24)(25). Chil1 was recently reported to signal through the cell surface receptor IL-13 receptor ␣2 (IL-13R␣2) (26).…”

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confidence: 99%

Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia

et al. 2016

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dPseudomonas aeruginosa causes hospital-acquired pneumonia and is associated with high mortality. An effective response to such an infection includes efficient clearance of pathogenic organisms while limiting collateral damage from the host inflammatory response, known as host resistance and host tolerance, respectively. P. aeruginosa expresses a type III secretion system (T3SS) needle complex that induces NLRC4 (NOD-like receptor C4) activation, interleukin-1␤ (IL-1␤) production, and host tissue damage. Chitinase 3-like-1 (Chil1) is expressed during infection and binds to its receptor, IL-13 receptor ␣2 (IL-13R␣2), to regulate the pathogen-host response during Streptococcus pneumoniae infection, but the role Chil1 plays in balancing the host resistance and host tolerance during P. aeruginosa pneumonia is not known. We conducted experiments using C57BL/6 mice with or without a genetic deficiency of Chil1 and demonstrated that Chil1-deficient mice succumb to P. aeruginosa infection more rapidly than the wild type (WT). The decreased survival time in infected Chil1-deficient mice is associated with more neutrophils recruited to the airways, more lung parenchymal damage, and increased pulmonary consolidation while maintaining equivalent bacterial killing compared to WT mice. Infected Chil1-deficient mice and bone marrow-derived macrophages (BMDMs) from Chil1-deficient mice have increased production of tumor necrosis factor alpha (TNF-␣) and IL-1␤ compared to infected WT mice and macrophages. Infection of Chil1-deficient BMDMs with non-NLRC4-triggering P. aeruginosa, which is deficient in the T3SS needle complex, did not alter the excessive IL-1␤ production compared to BMDMs from WT mice. The addition of recombinant Chil1 decreases the excessive IL-1␤ production but only partially rescues stimulated BMDMs from IL-13R␣2-deficient mice. Our data provide mechanistic insights into how Chil1 regulates P. aeruginosa-induced host responses. Hospital-acquired pneumonia is a common cause of hospitalassociated death and morbidity (1, 2). Pseudomonas aeruginosa causes both acute and chronic respiratory infections. P. aeruginosa is a common cause of opportunistic infection in hospitalized patients and is known to chronically colonize patients with structural lung diseases, such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD), as opposed to nonstructural lung diseases, such as pulmonary edema, chronic thrombotic disease, or atelectasis (3, 4). Acute lower respiratory tract infections caused by P. aeruginosa can lead to severe complications, such as acute respiratory distress syndrome (ARDS) and sepsis (5, 6). The clinical outcomes associated with P. aeruginosa pneumonia are the product of the immune system's ability to recognize and clear pathogenic organisms, known as host resistance (7-9). Recent investigations have led to a better appreciation that the pathogen-mediated immune response also causes collateral damage to host tissues independently of the bacterial burden, which also can contr...

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Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

Cited by 64 publications

References 66 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia

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