Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Rα, IL-13Rα1, and γc regulates relative cytokine sensitivity

Junttila, Ilkka; Mizukami, Kiyoshi; Dickensheets, Harold; Meier‐Schellersheim, Martin; Yamane, Hidehiro; Donnelly, Raymond P.; Paul, William E.

doi:10.1084/jem.20080452

Cited by 135 publications

(135 citation statements)

References 54 publications

(47 reference statements)

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“…3C). This fits with the concept that monocytes are more sensitive to IL-4 than IL-13 (35). The high levels of IL-4 after activation of iNKT cells in our short-term spleen culture (Fig.…”

Section: Discussionsupporting

confidence: 89%

Activation of Invariant NKT Cells in Early Phase of Experimental Autoimmune Encephalomyelitis Results in Differentiation of Ly6Chi Inflammatory Monocyte to M2 Macrophages and Improved Outcome

Denney

Kok

Cole

et al. 2012

The Journal of Immunology

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Neuropathology in multiple sclerosis is closely linked to presence of macrophages in the CNS. Both M1 (inflammatory) and M2 (alternatively activated, noninflammatory) macrophages are found in the inflamed CNS and thought to differentiate from infiltrating monocytes. It is unclear whether the balance of M1 and M2 macrophages can be altered and whether this affects disease outcome. We show in this article that Ly6Chi inflammatory monocytes are the early and dominant infiltrating cells in the CNS during experimental autoimmune encephalomyelitis, a model for the acute phase of multiple sclerosis. Activation of invariant NKT (iNKT) cells reduced the frequency of Ly6Chi monocytes and increased the proportion of M2 macrophages in the CNS with associated improvement in neurologic impairment. In contrast, iNKT-deficient mice showed higher numbers of Ly6Chi monocytes, reduced M2, and much more severe disease. Adoptive transfer of M2-enriched cells to iNKT-deficient mice markedly improved neurologic impairment. In vitro and in vivo experiments showed that iNKT cells promote differentiation of monocytes to M2 macrophages in an IL-4 and CD1d-dependent process. These findings indicate that infiltrating Ly6Chi inflammatory monocytes are early players in acute neuroinflammation and that their frequency and differentiation can be influenced by activation of iNKT cells with resultant improvement in disease outcome.

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“…3C). This fits with the concept that monocytes are more sensitive to IL-4 than IL-13 (35). The high levels of IL-4 after activation of iNKT cells in our short-term spleen culture (Fig.…”

Section: Discussionsupporting

confidence: 89%

Activation of Invariant NKT Cells in Early Phase of Experimental Autoimmune Encephalomyelitis Results in Differentiation of Ly6Chi Inflammatory Monocyte to M2 Macrophages and Improved Outcome

Denney

Kok

Cole

et al. 2012

The Journal of Immunology

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“…***P , 0.001. and consequent intranasal OVA challenge, Relm-a expression is predominantly IL-13Ra1-independent, whereas after mucosal sensitization and challenge (using Asp extract), the expression of Relm-a was IL-13Ra1-dependent. Whereas airway epithelial cells predominantly express Type II IL-4R, which mediates IL-4 and IL-13 signaling, infiltrating hematopoietic cells predominantly express Type I IL-4R (40). Indeed, we demonstrate that after allergen challenge, Relm-a is expressed by both airway epithelial cells and macrophages.…”

Section: Discussionmentioning

confidence: 63%

Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

Munitz

Cole²,

Karo‐Atar³

et al. 2012

Am J Respir Cell Mol Biol

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Resistin-like molecule a (Relm-a) is one of the most up-regulated gene products in allergen-and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-a was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-a production, and the role of Relm-a after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-a was secreted into the airway lumen, dependent on both the IL-13 receptora1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene-targeted mice demonstrate that Relm-a was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-a in the lungs. The differential regulation of Relm-a expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm-a in acute experimental models of allergen-associated Th2 immune responses.Keywords: resistin-like molecule-a; asthma; IL-4; Asthma is a chronic and complex inflammatory disease of the airways characterized by airflow obstruction, mucus production, airway hyperresponsiveness (AHR), and airway inflammation. It is the most common chronic illness of childhood, affecting up to 20% of children and 7% of adults in Western countries, with a combined prevalence of approximately 300 million people worldwide (1).Asthmatic responses are associated with increased numbers of pulmonary inflammatory cells, including activated T-lymphocytes and eosinophils, which correlate with disease severity (2, 3). T-lymphocytes of the Th2 phenotype are thought to induce asthma through the secretion of an array of cytokines, and in particular, IL-4 and IL-13 (4, 5). These cytokines are produced at elevated concentrations in allergic tissue, and are central regulators of many hallmark features of the disease, such as the production of IgE, Th2 differentiation, eosinophilia, mucus hypersecretion, chemokine induction, and airway hyperresponsiveness (AHR) (6). Notably, IL-13 is considered more of an effector cytokine in the pathogenesis of allergic airway disease compared with IL-4 because AHR and mucus production are predominantly I...

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“…sensitive to stimulation by IL-4 than IL-13 (28). Macrophages can be frozen and upon thawing retain their phenotype and function as defined by in vitro assays (29).…”

Section: Discussionmentioning

confidence: 99%

“…On d 3, fluorescence intensity was strongest in the peritoneal area of the M(IL-4)-treated mice ( Figure 4A), a pattern that was similar to d -2 just mechanistic studies: would M(IL-4)s suppress colitis in a manner equivalent to that observed with M(IL-4 + IL-13)s, and would cryopreserved M(IL-4)s retain their ability to inhibit colitis. It is generally accepted that IL-4 is the key cytokine in the alternative activation of macrophages and that IL-13 complements or enhances the differentiation of the AAM via STAT3 and STAT6 signaling (27,28). Assessment of canonical markers of mouse and human AAMs revealed almost identical responses to IL-4 and IL-4 + IL-13 (IL-13 alone was a less potent stimulus of an AAM phenotype), a finding in accordance with data showing that bone marrow-derived macrophages and human monocytes were more Indeed, we, and others, have shown that adoptive transfer of AAMs retrieved from mice or differentiated in vitro from bone marrow precursors or peritoneal macrophages can suppress colitis (14)(15)(16)(17)(18)(19)).…”

Section: Transferred M(il-4)s Localize To the Colon During Dnbs Colitismentioning

confidence: 99%

Cryopreserved Interleukin-4-Treated Macrophages Attenuate Murine Colitis in an Integrin β7-Dependent Manner

Leung

Petri

Reyes

et al. 2015

Mol Med

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The adoptive transfer of alternatively activated macrophages (AAMs) has proven to attenuate inflammation in multiple mouse models of colitis; however, the effect of cryopreservation on AAMs, the ability of previously frozen AAMs to block dinitrobenzene sulfonic acid (DNBS) (Th1) and oxazolone (Th2) colitis and their migration postinjection remains unknown. Here we have found that while cryopreservation reduced mRNA expression of canonical markers of interleukin (IL)-4-treated macrophages [M(IL-4)], this step did not translate to reduced protein or activity, and the cells retained their capacity to drive the suppression of colitis. The anticolitic effect of M(IL-4) adoptive transfer required neither T or B cell nor peritoneal macrophages in the recipient. After injection into the peritoneal cavity, M(IL-4)s migrated to the spleen, mesenteric lymph nodes and colon of DNBS-treated mice. The chemokines CCL2, CCL4 and CX3CL1 were expressed in the colon during the course of DNBS-induced colitis. The expression of integrin β7 on transferred M(IL-4)s was required for their anticolitic effect, whereas the presence of the chemokine receptors CCR2 and CX3CR1 were dispensable in this model. Collectively, the data show that M(IL-4)s can be cryopreserved M(IL-4)s and subsequently used to suppress colitis in an integrin β7-dependent manner, and we suggest that these proof-of-concept studies may lead to new cellular therapies for human inflammatory bowel disease.

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Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Rα, IL-13Rα1, and γc regulates relative cytokine sensitivity

Abstract: Interleukin (IL)-

Cited by 135 publications

References 54 publications

Activation of Invariant NKT Cells in Early Phase of Experimental Autoimmune Encephalomyelitis Results in Differentiation of Ly6Chi Inflammatory Monocyte to M2 Macrophages and Improved Outcome

Activation of Invariant NKT Cells in Early Phase of Experimental Autoimmune Encephalomyelitis Results in Differentiation of Ly6Chi Inflammatory Monocyte to M2 Macrophages and Improved Outcome

Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

Cryopreserved Interleukin-4-Treated Macrophages Attenuate Murine Colitis in an Integrin β7-Dependent Manner

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