Interleukin‐4 regulates proteoglycan‐induced arthritis by specifically suppressing the innate immune response

Cao, Yong; Brombacher, Frank; Tunyogi-Csapó, Miklós; Glant, Tibor T.; Finnegan, Alison

doi:10.1002/art.22422

Cited by 35 publications

(31 citation statements)

References 42 publications

(38 reference statements)

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“…These studies, however, did not directly address the cell population targeted by IL-4. Consistent with our results, Cao et al showed that IL-4Rα signaling in myeloid cells indeed has a potent anti-inflammatory activity in the proteoglycans-induced arthritis model (32). The IL-4Rα forms a heterodimer with either the common cytokine receptor gamma chain (γ c /CD132) or IL-13Rα1 (CD213a1), making type 1 and 2 IL-4R, respectively.…”

Section: Resultssupporting

confidence: 92%

Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling

Wermeling

Anthony

Brombacher

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The anti-inflammatory drug high-dose intravenous immunoglobulin, widely used to suppress inflammation, depends on a specific α-2,6-sialylated glycoform of IgG Fc to induce Interleukin 4 (IL-4) and Signal Transducer and Activator of Transcription 6 (STAT6) signaling for its activity. Here we show that anti-inflammatory activities of IL-4 can be attributed to the direct action of this cytokine on myeloid effector cells, depending on their expression of the IL-4 receptor alpha chain (IL-4Rα/CD124). However, in their basal state, these cells express low levels of IL-4Rα and would not be expected to result in significant signaling compared with other cell populations. This apparent paradox can be explained by the observation that during inflammation, triggered by a variety of stimuli (including autoantibodies, adjuvants, and TLR ligands), IL-4Rα is up-regulated specifically on these cells, priming them for STAT6 signaling. The regulation is mediated by a soluble, proteinase K-sensitive factor, released to the circulation by bone marrow-derived, non-B/non-T cells found in several organs, including the lungs, and fat. We propose that this regulation is part of a homeostatic mechanism to limit excessive inflammation and tissue damage. High-dose intravenous immunoglobulin thus exploits an endogenous feedback loop, general to inflammation, that could be further targeted for therapeutic purposes.

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Section: Resultssupporting

confidence: 92%

Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling

Wermeling

Anthony

Brombacher

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Tissue repair Increase of extracellular matrix remodelling and fibrogenesis Gratchev et al (2001) m Angiogenesis Goerdt et al (1993), Kodelja et al (1997) Modulation of inflammation mAnti-inflammatory cytokines kPro-inflammatory cytokines Modulation of the IL-27R Bonder et al (1998), Cheung et al (1990), Fenton et al (1992), Ruckerl et al (2006), Schebesch et al (1997), and Turnbull et al (2006) Protection of the host from unwanted inflammation during Pathology Placenta, lung Rheumatoid arthritis Psoriasis Alzheimer's disease Autoimmune encephalomyelitis Cao et al (2007), Colton et al (2006), Djemadji-Oudjiel et al (1996), Finnegan et al (2002), Goerdt et al (1993), Ponomarev et al (2007), and Szekanecz et al (1994) Ag presentation m MHCII expression Cua and Stohlman (1997) Recognition and uptake of glycoproteins and cancer cells Ichii et al (2000) and Kawakami et al (1994) Cheung et al, 1990). Moreover, AAMF selectively increase production of macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC), inducing recruitment of antigen presenting cells to the site of inflammation (Bonecchi et al, 1998;Mantovani et al, 2000).…”

Section: Role Referencementioning

confidence: 98%

Alternative activation of macrophages: Immune function and cellular biology

2009

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“…Production of TGFb1 by alternatively activated macrophages has been documented (29), and the cells have been implicated in tissue repair and remodeling (30) and in protection of the host from damaging inflammation during pathology (31,32). In the context of pneumococcal nasopharyngeal colonization, they may limit inflammation to prevent tissue damage and thus promote prolonged carriage.…”

Section: Discussionmentioning

confidence: 99%

Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells

Neill

Coward

Gritzfeld

et al. 2014

Am J Respir Crit Care Med

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Rationale: Nasopharyngeal carriage of Streptococcus pneumoniae is a prerequisite for invasive disease, but the majority of carriage episodes are asymptomatic and self-resolving. Interactions determining the development of carriage versus invasive disease are poorly understood but will influence the effectiveness of vaccines or therapeutics that disrupt nasal colonization.Objectives: We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage.Methods: Pneumococcal interactions with human nasopharyngeal and bronchial fibroblasts and epithelial cells were investigated in vitro. A murine model of nasopharyngeal carriage and an experimental human pneumococcal challenge model were used to characterize immune responses in the airways during carriage. Measurements and Main Results:We describe the previously unknown immunological basis of noninvasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active transforming growth factor (TGF)-b1 by S. pneumoniae in human host cells and highlight the key role for TGF-b1 and T regulatory cells in the establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGF-b1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-b1 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-b1 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx.Conclusions: These data explain the mechanisms by which S. pneumoniae colonize the human nasopharynx without inducing damaging host inflammation and provide insight into the role of bacterial and host constituents that allow and maintain carriage.

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Interleukin‐4 regulates proteoglycan‐induced arthritis by specifically suppressing the innate immune response

Cited by 35 publications

References 42 publications

Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling

Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling

Alternative activation of macrophages: Immune function and cellular biology

Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells

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