Chitinase-3-like protein 1 protects skeletal muscle from TNFα-induced inflammation and insulin resistance

Görgens, Sven W.; Eckardt, Kristin; Elsen, Manuela; Tennagels, Norbert; Eckel, Jürgen

doi:10.1042/bj20131151

Cited by 52 publications

(64 citation statements)

References 38 publications

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“…To function as an immunomodulator, it is expected to transmit its signal through a cell surface receptor. There are two presumable receptors of CHI3L1, IL-13R␣2 (34) and protease-activated receptor 2 (PAR2) (35). CHI3L1 was shown to play a critical role in antipneumococcal responses, including augmenting bacterial clearance (23) in an IL-13R␣2-dependent manner (34).…”

Section: Resultsmentioning

confidence: 99%

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Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses

Gao

2015

Infect Immun

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Chitinase 3-like 1 (CHI3L1) has been shown to play a role in promoting antibacterial responses, decreasing tissue injury, and enhancing pulmonary repair. This study sought to elucidate the role of CHI3L1 in augmenting the corneal innate immune response to Candida albicans infection in an animal model of fungal keratitis. Flagellin applied topically 24 h prior to C. albicans inoculation significantly protected the corneal from C. albicans and induced CHI3L1 expression in C57BL/6 mouse corneas. CHI3L1, however, played a detectable but minor role in flagellin-induced protection. While C. albicans keratitis was more severe in the corneas treated with Chi3l1 small interfering RNA (siRNA), corneas treated with recombinant CHI3L1 before C. albicans inoculation had markedly ameliorated keratitis, reduced fungal load, and decreased polymorphonucleocyte (PMN) infiltration in an interleukin 13 receptor ␣2 (IL-13R␣2)-dependent manner. CHI3L1 treatment resulted in the induction of the antimicrobial peptides ␤-defensin 3, CRAMP, and chemokine CXCL10 and its receptor CXCR3 in corneal epithelial cells. Importantly, CHI3L1 administered after C. albicans inoculation also had strong protection against fungal keratitis, suggesting a therapeutic window. This is the first report demonstrating that CHI3L1 is induced during fungal infection, where it acts as an immunomodulator to promote fungal clearance and to regulate antifungal innate immune responses in the cornea.T he cornea's visual properties are exquisitely sensitive to inflammation-mediated damage. The cornea is an immuneprivileged site with multiple anatomical, physiological, and immunoregulatory processes that inhibit many innate and adaptive immune responses (1, 2). As such, a normal cornea is remarkably resistant to infection. However, when the epithelial barrier function is breached (3), which may occur during routine contact lens wear, opportunistic pathogens such as bacteria and fungi gain access to the deeper cellular layers of the epithelium and colonize the cornea (4). This leads to the engagement of intraepithelially expressed Toll-like receptors (TLRs) with invading pathogens (5), resulting in the abrogation of immune privilege and the reactivation of the innate immune response (6). Candida albicans is one such opportunistic pathogen that may cause corneal infection following trauma or surgery or under immunosuppressive conditions, such as the prolonged use of corticosteroids and topical anesthetic abuse (7-12). Although the fungal keratitis is rare, the incidence has increased in recent years, especially in contact lens wearers (13,14). To date, there is no clinically amenable measure to prevent fungal keratitis. Current practice in treating fungal keratitis involves the use of topical antifungal drops, such as natamycin and amphotericin B. Topical antifungals can have toxic effects, such as punctate keratitis and recurrent corneal epithelial erosions (15). Hence, understanding the pathogenesis of fungal keratitis and host responses will aid in identifying new the...

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Section: Resultsmentioning

confidence: 99%

“…CHI3L1 was reported to protect skeletal muscle from TNF-␣-induced inflammation and insulin resistance and to induce mucin-5AC production in human bronchial epithelial cells via protease-activated receptor 2 (35,41). Hence, CHI3L1 may signal via different pathways in a cell-and/or tissue-specific manner.…”

Section: Figmentioning

confidence: 99%

Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses

Gao

2015

Infect Immun

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“…Very recently, our group identified chitinase-3-like protein 1 (CHI3L1) as a novel myokine [88]. Interestingly, plasma CHI3L1 levels are upregulated in patients with insulin resistance and type 2 diabetes, independently of obesity [89].…”

Section: Myokines and Metabolic Regulationmentioning

confidence: 99%

“…Our in vitro experiments have shown that the expression and release of CHI3L1 is stimulated by proinflammatory cytokines such as TNFα. We have reported evidence that CHI3L1 protects myotubes from TNFα-induced insulin resistance and inflammation by inhibiting NFκB activation, suggesting that CHI3L1 is an auto-protective factor that is induced upon demand to protect skeletal muscle from the negative impact of TNFα [88].…”

Section: Myokines and Metabolic Regulationmentioning

confidence: 99%

Myokines in insulin resistance and type 2 diabetes

et al. 2014

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Skeletal muscle represents the largest organ of the body in non-obese individuals and is now considered to be an active endocrine organ releasing a host of so-called myokines. These myokines are part of a complex network that mediates communication between muscle, the liver, adipose tissue, the brain and other organs. Recent data suggest that myokines regulated by muscle contraction may play a key role in mediating the health-promoting effects of regular physical activity. Although hundreds of myokines have recently been described in proteomic studies, we currently have a rather limited knowledge of the specific role these myokines play in the prevention of insulin resistance, inflammation and associated metabolic dysfunction. Several myokines are known to have both local and endocrine functions, but in many cases the contribution of physical activity to the systemic level of these molecules remains as yet unexplored. Very recently, novel myokines such as irisin, which is thought to induce a white to brown shift in adipocytes, have gained considerable interest as potential therapeutic targets. In this review, we summarise the most recent findings on the role of myokines in the regulation of substrate metabolism and insulin sensitivity. We further explore the role of myokines in the regulation of inflammation and provide a critical assessment of irisin and other myokines regarding their potential as therapeutic targets.

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“…The pro- Also expressed in type II muscle fibers (550) Depolarization of plasma membrane (712) Na ϩ -current inhibition, left shift of Na ϩ channel activation and inactivation (274) Activation of PKC-mediated Na ϩ channel phosphorylation (148) Induces muscle proteolysis and atrophy (148) Alters resting Ca 2ϩ levels (decrease in myotubes) (741) No change in tetanic Ca 2ϩ amplitudes in muscle fibers (741) Decreases Ca 2ϩ transient amplitudes by 50% (in myotubes) (741) Depresses tetanic force production in limb and diaphragm muscle (571) Activates ubiquitin-proteasome pathway (227,428) Increase major histocompatibility complex II surface expression (in combination with IFN-␥) in human muscle cells (359) Activation of NF-B (573) Downregulation of MyoD inhibits myogenic differentiation (280) Induces insulin resistance in muscle (248) Stimulates IL-6 production in skeletal muscle cells (IL-1␤) (445) Stimulates prostaglandin E 2 (PGE2) production and proteolysis (250) Ubiquitin gene expression 1 (437) or % (228)…”

Section: B Tnf-␣ Muscle Atrophy and Contractile Dysfunctionmentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

273

298

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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Chitinase-3-like protein 1 protects skeletal muscle from TNFα-induced inflammation and insulin resistance

Cited by 52 publications

References 38 publications

Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses

Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses

Myokines in insulin resistance and type 2 diabetes

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

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