scholarly journals SIRPα sequesters SHP-2 to promote IL-4/13 signaling and alternative activation of macrophages

2021 ◽  
Author(s):  
Lei Shi ◽  
Koby Kidder ◽  
Zhen Bian ◽  
Samantha Kuon Ting Chiang ◽  
Corbett Ouellette ◽  
...  
Keyword(s):  
Wound Healing ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Alternative Activation ◽  
Activated Macrophages ◽  
Negative Regulators ◽  
Impaired Wound Healing ◽  
Alternatively Activated Macrophages ◽  
Arginase 1 ◽  
Alternatively Activated

The Th2 cytokines IL-4 and IL-13 through activation of their shared receptor IL-4Rα direct macrophage alternative activation to promote immunosuppression and wound healing. However, the mechanisms that control macrophage responses to IL-4/13 are not fully understood. Apart from driving JAK-STAT and PI3K-Akt pathways to polarize macrophages toward the alternative phenotype, the activated IL-4/13 receptors recruit negative regulators SHP-1 and SHP-2, which dephosphorylate IL-4Rα and decrease its signaling. Here we report that SIRPα spatially restricts SHP-2 and, by such, promotes IL-4/13 signaling and macrophage alternative activation. SIRPα executes this regulation via its cytoplasmic ITIMs/ITSMs that undergo phosphorylation by IL-4/13-induced, Src kinase-activated Brutons tyrosine kinase (Btk), resulting in recruitment of SHP-2 and preclusion of SHP-2 from binding to and inhibiting IL-4/13 receptors. Despite that this regulation occurs independent of CD47, extracellular CD47 ligation of SIRPα facilitates its cytoplasmic phosphorylation and SHP-2 sequestration, leading to stronger IL-4/13 signaling and enhanced macrophage expression of IL-10, TGFβ, CD206, arginase-1, etc. Conversely, deficiency of SIRPα allows SHP-2 to freely bind to γC or IL-13Rα1 and through which dephosphorylate IL-4Rα, dampening its signaling. Consistent with these findings, impaired wound healing in Sirpα-/- mice under experimental colitis correlated with a deficit of immunosuppressive macrophages in the colon, a condition that was corrected by transfusion of ex vivo-produced SIRPαhigh alternatively activated macrophages.

scholarly journals Arginase in Parasitic Infections: Macrophage Activation, Immunosuppression, and Intracellular Signals

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Cinthia C. Stempin ◽  
Laura R. Dulgerian ◽  
Vanina V. Garrido ◽  
Fabio M. Cerban
Keyword(s):  
Macrophage Activation ◽  
Transforming Growth Factor ◽  
Parasite Clearance ◽  
Alternative Activation ◽  
Parasitic Infections ◽  
Activated Macrophages ◽  
Proinflammatory Response ◽  
Alternatively Activated Macrophages ◽  
Arginase 1

A type 1 cytokine-dependent proinflammatory response inducing classically activated macrophages (CaMϕs) is crucial for parasite control during protozoan infections but can also contribute to the development of immunopathological disease symptoms. Type 2 cytokines such as IL-4 and IL-13 antagonize CaMϕs inducing alternatively activated macrophages (AaMϕs) that upregulate arginase-1 expression. During several infections, induction of arginase-1-macrophages was showed to have a detrimental role by limiting CaMϕ-dependent parasite clearance and promoting parasite proliferation. Additionally, the role of arginase-1 in T cell suppression has been explored recently. Arginase-1 can also be induced by IL-10 and transforming growth factor-β(TGF-β) or even directly by parasites or parasite components. Therefore, generation of alternative activation states of macrophages could limit collateral tissue damage because of excessive type 1 inflammation. However, they affect disease outcome by promoting parasite survival and proliferation. Thus, modulation of macrophage activation may be instrumental in allowing parasite persistence and long-term host survival.

Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4664-4674 ◽  
Author(s):  
Jan Van den Bossche ◽  
Pieter Bogaert ◽  
Jolanda van Hengel ◽  
Christopher J. Guérin ◽  
Geert Berx ◽  
...  
Keyword(s):  
Allergic Airway Inflammation ◽  
Interleukin 4 ◽  
Cell Contact ◽  
Cellular Interactions ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Arginase 1 ◽  
Heterotypic Interactions ◽  
Alternatively Activated ◽  
E Cadherin

Abstract Alternatively activated macrophages (AAMs), triggered by interleukin-4 (IL-4) and IL-13, play a modulating role during Th2 cytokine-driven pathologies, but their molecular armament remains poorly characterized. Here, we established E-cadherin (Cdh1) as a selective marker for IL-4/IL-13–exposed mouse and human macrophages, which is STAT6-dependently induced during polarized Th2 responses associated with Taenia crassiceps helminth infections or allergic airway inflammation. The IL-4–dependent, arginase-1/ornithine decarboxylase–mediated production of polyamines is important for maximal Cdh1 induction, unveiling a novel mechanism for IL-4–dependent gene transcription. At the macrophage surface, E-cadherin forms a functional complex with the catenins that accumulates at sites of cell contact. Macrophage-specific deletion of the Cdh1 gene illustrates the implication of E-cadherin in IL-4–driven macrophage fusion and heterotypic interactions with CD103+ and KLRG1+ T cells. This study identifies the E-cadherin/catenin complex as a discriminative, partly polyamine-regulated feature of IL-4/IL-13–exposed alternatively activated macrophages that contributes to homotypic and heterotypic cellular interactions.

scholarly journals Extraintestinal Helminth Infection Limits Pathology and Proinflammatory Cytokine Expression during DSS-Induced Ulcerative Colitis: A Role for Alternatively Activated Macrophages and Prostaglandins

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Yadira Ledesma-Soto ◽  
Blanca E. Callejas ◽  
César A. Terrazas ◽  
Jose L. Reyes ◽  
Arlett Espinoza-Jiménez ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Activity Index ◽  
Disease Activity Index ◽  
Helminth Parasites ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Arginase 1 ◽  
Alternatively Activated

Chronic inflammation of the intestinal mucosa is characteristic of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. Helminth parasites have developed immunomodulatory strategies that may impact the outcome of several inflammatory diseases. Therefore, we investigated whetherTaenia crassicepsinfection is able to decrease the inflammatory effects of dextran sulfate sodium- (DSS-) induced ulcerative colitis in BALB/c and C57BL/6 mice. Preinfection significantly reduced the manifestations of DSS-induced colitis, as weight loss and shortened colon length, and decreased the disease activity index independently of the genetic background of the mice.Taeniainfection decreased systemic levels of proinflammatory cytokines while increasing levels of IL-4 and IL-10, and the inflammatory infiltrate into the colon was also markedly reduced. RT-PCR assays from colon showed thatT. crassiceps-infected mice displayed increased expression of Arginase-1 but decreased expression of iNOS compared to DSS-treated uninfected mice. The percentages of T regulatory cells were not increased. The adoptive transfer of alternatively activated macrophages (AAMФs) from infected mice into mice with DSS-induced colitis reduced the severity of colon inflammation. Administration of indomethacin abrogated the anticolitic effect ofTaenia. Thus,T. crassicepsinfection limits the pathology of ulcerative colitis by suppressing inflammatory responses mechanistically associated with AAMФs and prostaglandins.

scholarly journals Utilization of Host Polyamines in Alternatively Activated Macrophages Promotes Chronic Infection byBrucella abortus

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Tobias Kerrinnes ◽  
Maria G. Winter ◽  
Briana M. Young ◽  
Vladimir E. Diaz-Ochoa ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Chronic Infection ◽  
Intracellular Survival ◽  
Interleukin 4 ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Content Type ◽  
Arginase 1 ◽  
Long Course ◽  
Multiple Drugs ◽  
Alternatively Activated

ABSTRACTTreatment of intracellular bacterial pathogens with antibiotic therapy often requires a long course of multiple drugs. A barrier to developing strategies that enhance antibiotic efficacy against these pathogens is our poor understanding of the intracellular nutritional environment that maintains bacterial persistence. The intracellular pathogenBrucella abortussurvives and replicates preferentially in alternatively activated macrophages (AAMs); however, knowledge of the metabolic adaptations promoting exploitation of this niche is limited. Here we show that one mechanism promoting enhanced survival in AAMs is a shift in macrophage arginine utilization from production of nitric oxide (NO) to biosynthesis of polyamines, induced by interleukin 4 (IL-4)/IL-13 treatment. Production of polyamines by infected AAMs promoted both intracellular survival ofB. abortusand chronic infection in mice, as inhibition of macrophage polyamine synthesis or inactivation of the putative putrescine transporter encoded bypotIHGFreduced both intracellular survival in AAMs and persistence in mice. These results demonstrate that increased intracellular availability of polyamines induced by arginase-1 expression in IL-4/IL-13-induced AAMs promotes chronic persistence ofB. abortuswithin this niche and suggest that targeting of this pathway may aid in eradicating chronic infection.

scholarly journals Identification of Caspase-6 as a New Regulator of Alternatively Activated Macrophages

2016 ◽  
Vol 291 (33) ◽  
pp. 17450-17466 ◽  
Author(s):  
Yongfang Yao ◽  
Qian Shi ◽  
Bing Chen ◽  
Qingsong Wang ◽  
Xinda Li ◽  
...  
Keyword(s):  
Cell Invasion ◽  
Protein Composition ◽  
Alternative Activation ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Protein Levels ◽  
Caspase 6 ◽  
Alternatively Activated

Alternatively activated macrophages (AAMs) play essential roles in the promotion of tissue remodeling, vasculogenesis, and tumor progression; however, the detailed mechanisms underlying the activation of AAMs remain largely unknown. Here, by using quantitative proteomic analysis, we identified 62 proteins that were up-regulated in IL-4-induced macrophages. Among these, Caspase-6 was increased significantly. Caspase-6 is important in the apoptotic signaling pathway; however, its role in non-apoptosis is also reported. Here, we first examined the non-apoptotic role of Caspase-6 in the alternative activation of macrophages after administration of IL-4, 4T1 tumor conditional medium, or co-culture with 4T1 cells. Both treatments promoted alternative activation of RAW264.7 cells and primary macrophages, whereas disruption of caspase-6 expression and activity could markedly suppress the biomarker levels of AAMs. Overexpression of Caspase-6 could significantly promote the activation of AAMs. Importantly, we further present evidence that caspase-6 could regulate breast cancer cell invasion by modulating MMP-2 and MMP-9 expression in 4T1 tumor-associated macrophages, as ablation of protein levels or activity of caspase-6 suppressed tumor cell invasion in vitro. In conclusion, the observed results markedly expanded our views of the dynamic changes in protein composition during alternative activation of macrophages, and they revealed a critical new role of caspase-6 in regulating this cellular biological process, which suggested that caspase-6 might be a key nod molecule to regulate immunological steady-state and be a therapeutic candidate for tumor immunotherapy.

scholarly journals Possible Role for Toll-Like Receptors in Interaction of Fasciola hepatica Excretory/Secretory Products with Bovine Macrophages

2007 ◽  
Vol 76 (2) ◽  
pp. 678-684 ◽  
Author(s):  
Robin J. Flynn ◽  
Grace Mulcahy
Keyword(s):  
Fasciola Hepatica ◽  
Interleukin 10 ◽  
Alternative Activation ◽  
Alternatively Activated Macrophages ◽  
Purified Protein Derivative ◽  
Arginase 1 ◽  
Secretory Products ◽  
Kinetics Of ◽  
Alternatively Activated

ABSTRACT Alternative activation of macrophages (Mφ) during helminth infection is a characteristic feature of the host immune response. Alternatively activated macrophages (AAMφ) are distinguished from others by high arginase 1 (Arg-1) activity, low nitric oxide (NO), and high interleukin 10 (IL-10) production. In murine models, these cells have been shown to possess anti-inflammatory properties. They have also been implicated in exacerbating a subsequent infection with a secondary pathogen. In this study we used cattle experimentally infected with Fasciola hepatica to monitor the kinetics of IL-4 and IL-10 over the course of infection. Using naïve Mφ in vitro, we examined the effects of exposure to F. hepatica excretory/secretory products (FhepES) alone or in combination with IL-4. Our results suggest that FhepES may work in combination with IL-4 to produce AAMφ. The effects of FhepES on the subsequent responses to lipopolysaccharide (LPS) and purified protein derivative from Mycobacterium bovis (PPD-B), which are bovine Toll-like receptor 4 (TLR4) and TLR2 antagonists, respectively, were also examined. We found that Mφ stimulated with FhepES together with LPS or PPD-B have reduced NO or gamma interferon production, respectively. The ability of FhepES to produce AAMφ was found to be heat labile and partially dependent on glycan residues. A possible role for TLR recognition is discussed.

Bone marrow-derived alternatively activated macrophages reduce colitis without promoting fibrosis: participation of IL-10

2013 ◽  
Vol 304 (9) ◽  
pp. G781-G792 ◽  
Author(s):  
Gabriella Leung ◽  
Arthur Wang ◽  
Maria Fernando ◽  
Van C. Phan ◽  
Derek M. McKay
Keyword(s):  
Bone Marrow ◽  
Ex Vivo ◽  
Smooth Muscle Actin ◽  
Activated Macrophages ◽  
Wild Type ◽  
Alternatively Activated Macrophages ◽  
Murine Colitis ◽  
Additional Support ◽  
Biochemical Assessment ◽  
Alternatively Activated

Alternatively activated macrophages (AAMs) (or M2a) can inhibit colitis but may also be associated with fibrosis. Thus, by using the dinitrobenzene sulfonic (DNBS) murine model of colitis, this study aimed to determine whether 1) bone marrow (BM)-derived AAMs could reduce colitis, 2) any anticolitic effect of BM-AAMs was IL-10 dependent, and 3) repeated AAM treatments remained effective and were associated with fibrosis in the gut or other tissues. Balb/c mice received AAMs (106 intraperitoneally) from wild-type (WT) or IL-10−/− mice 48 h prior to DNBS (3 mg intrarectally) with disease assessed 72 h later, or they received three doses of DNBS at 2-wk intervals ± AAMs 6 h post-DNBS to mimic a treatment regimen. DNBS-treated mice developed colitis; this was significantly less severe in mice receiving WT AAMs and less so in animals given IL-10−/− AAMs, indicating a role for IL-10 in the inhibition of DNBS-driven colitis. Similarly, after the third AAM treatment lesser colonic histopathology was observed compared with time-matched DNBS-only-treated animals, and notably there was no evidence of increased fibroses in the colon, terminal ileum, lung, or liver of AAM-treated mice as assessed by quantitative PCR for prolyl-4-hydrolase, α-smooth muscle actin, and collagen (type IIIα) and histochemical and biochemical assessment of collagen deposition. This study provides mechanistic insight to the anticolitic capacity of AAMs and indicates that repeated adoptive transfer of ex vivo programmed BM-AAMs is safe and efficacious in the treatment of DNBS-induced murine colitis, providing additional support for their consideration as an immunotherapy.

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