IFN-β Acts on Monocytes to Ameliorate CNS Autoimmunity by Inhibiting Proinflammatory Cross-Talk Between Monocytes and Th Cells

Rasouli, Javad; Casella, Giacomo; Ishikawa, Larissa Lumi Watanabe; Thomé, Rodolfo; Boehm, Alexandra; Ertel, Adam; Melo‐Silva, Carolina R.; Mari, Elisabeth R.; Porazzi, Patrizia; Zhang, Weifeng; Xiao, Dan; Sigal, Luis J.; Fortina, Paolo; Zhang, Guang‐Xian; Rostami, Abdolmohamad; Ćirić, Bogoljub

doi:10.3389/fimmu.2021.679498

Cited by 9 publications

(7 citation statements)

References 72 publications

(90 reference statements)

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“…Granulocyte macrophage-colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine that can be expressed by both immune and tissue-resident cells (1)(2)(3)(4)(5)(6)(7)(8)(9). Among immune cells, T helper (Th) cells are the most abundant source of GM-CSF (2,10).…”

Section: Introductionmentioning

confidence: 99%

Transcription Factor RUNX3 Mediates Plasticity of ThGM Cells Toward Th1 Phenotype

et al. 2022

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GM-CSF-producing T helper (Th) cells play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Recent studies have identified a distinct population of GM-CSF-producing Th cells, named ThGM cells, that also express cytokines TNF, IL-2, and IL-3, but lack expression of master transcription factors (TF) and signature cytokines of commonly recognized Th cell lineages. ThGM cells are highly encephalitogenic in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Similar to Th17 cells, in response to IL-12, ThGM cells upregulate expression of T-bet and IFN-γ and switch their phenotype to Th1. Here we show that in addition to T-bet, TF RUNX3 also contributes to the Th1 switch of ThGM cells. T-bet-deficient ThGM cells in the CNS of mice with EAE had low expression of RUNX3, and knockdown of RUNX3 expression in ThGM cells abrogated the Th1-inducing effect of IL-12. Comparison of ThGM and Th1 cell transcriptomes showed that ThGM cells expressed a set of TFs known to inhibit the development of other Th lineages. Lack of expression of lineage-specific cytokines and TFs by ThGM cells, together with expression of TFs that inhibit the development of other Th lineages, suggests that ThGM cells are a non-polarized subset of Th cells with lineage characteristics.

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Section: Introductionmentioning

confidence: 99%

Transcription Factor RUNX3 Mediates Plasticity of ThGM Cells Toward Th1 Phenotype

et al. 2022

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“…Amplification of this autoimmune neuroinflammation by a feedback loop between monocytes and Th cells can be attenuated by IFN-β therapy, which results in indirect suppression of GM-CSF production by Th cells via increasing IL-10 expression by monocytes. This phenomenon underscores the critical role of monocyte and macrophage phenotype conversion in immune regulation ( 151 ). Furthermore, in a study on how morphology and function of both neutrophils and microglia affect the inflamed brain, a crosstalk with neutrophils extravasating to the brain parenchyma has been postulated to serve as an additional primer of macrophage-induced neuroinflammation ( 153 ).…”

Section: Implications For Covid-19mentioning

confidence: 73%

Weathering the Storm: Harnessing the Resolution of Inflammation to Limit COVID-19 Pathogenesis

2022

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The resolution of inflammation is a temporally and spatially coordinated process that in its innate manifestations, primarily involves neutrophils and macrophages. The shutdown of infection or injury-induced acute inflammation requires termination of neutrophil accumulation within the affected sites, neutrophil demise, and clearance by phagocytes (efferocytosis), such as tissue-resident and monocyte-derived macrophages. This must be followed by macrophage reprogramming from the inflammatory to reparative and consequently resolution-promoting phenotypes and the production of resolution-promoting lipid and protein mediators that limit responses in various cell types and promote tissue repair and return to homeostatic architecture and function. Recent studies suggest that these events, and macrophage reprogramming to pro-resolving phenotypes in particular, are not only important in the acute setting, but might be paramount in limiting chronic inflammation, autoimmunity, and various uncontrolled cytokine-driven pathologies. The SARS-CoV-2 (COVID-19) pandemic has caused a worldwide health and economic crisis. Severe COVID-19 cases that lead to high morbidity are tightly associated with an exuberant cytokine storm that seems to trigger shock-like pathologies, leading to vascular and multiorgan failures. In other cases, the cytokine storm can lead to diffuse alveolar damage that results in acute respiratory distress syndrome (ARDS) and lung failure. Here, we address recent advances on effectors in the resolution of inflammation and discuss how pro-resolution mechanisms with particular emphasis on macrophage reprogramming, might be harnessed to limit the universal COVID-19 health threat.

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“…Type I IFNs have been identified as an important therapeutic target because of their protective role in MS and EAE development (16)(17)(18)(19). IFN-a has also shown effectiveness in reducing MS relapses, although it is less effective than b-IFN (20).…”

Section: Discussionmentioning

confidence: 99%

Influence of Type I Interferons in Gammaherpesvirus-68 and Its Influence on EAE Enhancement

Márquez

Croft²,

Shanina³

et al. 2022

Front. Immunol.

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Epstein-Barr virus (EBV) has been identified as a putative trigger of multiple sclerosis (MS). Previously, we reported that mice latently infected with murine gammaherpesvirus 68 (γHV-68), the murine homolog to EBV, and induced for experimental autoimmune encephalomyelitis (EAE), developed an enhanced disease more reminiscent of MS. These prior results showed that expression of CD40 on CD11b+CD11c+ cells in latently infected mice was required to prime the strong Th1 response driving disease as well as decreasing Treg frequencies in the periphery and CNS. Subsequent work demonstrated that transfer of B cells from latently infected mice was sufficient to enhance disease. Herein, we show that B cells from infected mice do not need type I IFN signaling to drive a strong Th1 response, yet are important in driving infiltration of the CNS by CD8+ T cells. Given the importance of type I IFNs in MS, we used IFNARko mice in order to determine if type I IFN signaling was important in the enhancement of EAE in latently infected mice. We found that while type I IFNs are important for the control of γHV-68 infection and maintenance of latency, they do not have a direct effect in the development of enhanced EAE.

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IFN-β Acts on Monocytes to Ameliorate CNS Autoimmunity by Inhibiting Proinflammatory Cross-Talk Between Monocytes and Th Cells

Cited by 9 publications

References 72 publications

Transcription Factor RUNX3 Mediates Plasticity of ThGM Cells Toward Th1 Phenotype

Transcription Factor RUNX3 Mediates Plasticity of ThGM Cells Toward Th1 Phenotype

Weathering the Storm: Harnessing the Resolution of Inflammation to Limit COVID-19 Pathogenesis

Influence of Type I Interferons in Gammaherpesvirus-68 and Its Influence on EAE Enhancement

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