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RGS2 is an innate immune checkpoint for suppressing Gαq mediated IFNγ generation and lung injury

ABSTRACT: Infections can trigger the release of IFNγ, a type II interferon, which exacerbates tissue inflammation and may lead to severe acute lung injury (ALI). However, the regulatory mechanisms of IFNγ production in the lungs are not fully understood. In this study, we identified RGS2 as a crucial regulator of IFNγ levels in the lungs during infection. The absence of RGS2 led to persistently elevated IFNγ production in macrophages, resulting in unresolved inflammatory lung damage. Notably, this effect was absent in RGS2-deficient chimeric mice that received wild-type bone marrow or RGS2 expression in alveolar macrophages (AMs), as well as in those treated with an IFNγ-blocking antibody. RGS2 exerts its regulatory role by inhibiting Gαq-mediated IFNγ production and inflammatory signaling in AMs. Consequently, the inhibition of Gαq in RGS2-deficient mice prevented IFNγ production in AMs and shifted their transcriptomic profile from an inflammatory to a reparative state. These findings suggest that the RGS2-Gαq signaling pathway could be a promising therapeutic target for mitigating inflammatory lung injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE276337 | GEO | 2024/09/04

REPOSITORIES: GEO

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Project description:Interferon (IFN)γ and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFNγ–priming and subsequent TLR4 activation induces so called classically activated macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4–treated macrophages, commonly called alternatively activated, are known to develop enhanced capacity for endocytosis, antigen presentation, and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4–dependent global gene activation program in IFNγ– versus IL-4–pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4– versus IFNγ–primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in alternatively primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNγ priming was actually found to suppress LPS–induced gene expression in a Stat1–dependent manner. Our data suggest that IL-4–priming is not per se anti-inflammatory but generates a macrophage that is “tissue protective” but still capable of mounting a strong inflammatory response after TLR4–dependent activation. Keywords: Gene expression profiling Gene expression was investigated in mouse bone marrow-derived macrophages (BMM). On day 7, BMM were stimulated with either IL-4 or IFNγ overnight (18h in total). LPS treatment was performed in primed and unprimed macrophages 4 h prior to harvesting. At least three independent experiments were performed for each condition.

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RGS2 is an innate immune checkpoint for suppressing Gαq mediated IFNγ generation and lung injury

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