High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage

Lee, Pui Y.; Nelson-Maney, Nathan; Huang, Yuelong; Levescot, Anaïs; Wang, Qiang; Wei, Kevin; Cunin, Pierre; Li, Yang; Lederer, James A.; Zhuang, Haoyang; Han, Sung‐Sik; Kim, Edy Y.; Reeves, Westley H.; Nigrović, Peter A.

doi:10.1172/jci.insight.129703

Cited by 20 publications

(20 citation statements)

References 62 publications

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“…In addition to Ly6c, the differential expression of C-C motif chemokine receptor 2 (Ccr2) and C-X3-C motif Chemokine Receptor 1 (Cx3cr1) separates these two monocyte subsets: Ly6c Hi classical monocytes are Ly6c Hi Ccr2 Hi Cx3cr1 int and Ly6c Lo non-classical monocytes are Ly6c Lo Ccr2 Lo Cx3cr1 Hi5 . Current studies support the idea that circulating Ly6c Hi classical monocytes are recruited to sites of inflammation and injury, where they perform pro-inflammatory functions 4,6,7 . It is also believed that Ly6c Hi classical monocytes transition into Ly6c Lo non-classical monocytes, which then promote anti-inflammatory and pro-reparative functions during inflammation 5 .…”

supporting

confidence: 72%

Ly6cLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation

Alkhani

Levy

Tsui

et al. 2020

Sci Rep

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Perinatal hepatic inflammation can have devastating consequences. Monocytes play an important role in the initiation and resolution of inflammation, and their diverse functions can be attributed to specific cellular subsets: pro-inflammatory or classical monocytes (Ly6c Hi ) and pro-reparative or non-classical monocytes (Ly6c Lo ). We hypothesized that inherent differences in Ly6c Hi classical monocytes and Ly6c Lo non-classical monocytes determine susceptibility to perinatal hepatic inflammation in late gestation fetuses and neonates. We found an anti-inflammatory transcriptional profile expressed by Ly6cLo non-classical monocytes, and a physiologic abundance of these cells in the late gestation fetal liver. Unlike neonatal pups, late gestation fetuses proved to be resistant to rhesus rotavirus (RRV) mediated liver inflammation. Furthermore, neonatal pups were rendered resistant to RRV-mediated liver injury when Ly6c Lo non-classical monocytes were expanded. Pharmacologic inhibition of Ly6c Lo non-classical monocytes in this setting restored susceptibility to RRV-mediated disease. These data demonstrate that Ly6c Lo monocytes promote resolution of perinatal liver inflammation in the late gestation fetus, where there is a physiologic expansion of non-classical monocytes, and in the neonatal liver upon experimental expansion of these cells. Therapeutic strategies directed towards enhancing Ly6c Lo nonclassical monocyte function may mitigate the detrimental effects of perinatal liver inflammation. open Scientific RepoRtS | (2020) 10:7165 | https://doi.

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supporting

confidence: 72%

Ly6cLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation

Alkhani

Levy

Tsui

et al. 2020

Sci Rep

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“…This continuous auto-Ab-mediated enhancement of the complement system also causes complement depletion and reduces the ability of phagocytes to remove dead cell debris, thus initiating a vicious circle ( 32 ). Intraperitoneal injection of pristane in B6 mice is an accepted model for lupus that simulates the SLE DAH pathological process ( 14 , 33 , 34 ). After injection, pristane migrates to the lungs, resulting in increased cell death, activation of inflammatory cells such as macrophages, activation of the classical pathway of complement and ICs formation and additionally alveolar hemorrhage similar to human DAH occurs.…”

Section: Discussionmentioning

confidence: 99%

PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion

Guo

Yaron

Wallen³

et al. 2021

Front. Cardiovasc. Med.

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Diffuse alveolar hemorrhage (DAH) is one of the most serious clinical complications of systemic lupus erythematosus (SLE). The prevalence of DAH is reported to range from 1 to 5%, but while DAH is considered a rare complication there is a reported 50–80% mortality. There is at present no proven effective treatment for DAH and the therapeutics that have been tested have significant side effects. There is a clear necessity to discover new drugs to improve outcomes in DAH. Serine protease inhibitors, serpins, regulate thrombotic and thrombolytic protease cascades. We are investigating a Myxomavirus derived immune modulating serpin, Serp-1, as a new class of immune modulating therapeutics for vasculopathy and lung hemorrhage. Serp-1 has proven efficacy in models of herpes virus-induced arterial inflammation (vasculitis) and lung hemorrhage and has also proved safe in a clinical trial in patients with unstable coronary syndromes and stent implant. Here, we examine Serp-1, both as a native secreted protein expressed by CHO cells and as a polyethylene glycol modified (PEGylated) variant (Serp-1m5), for potential therapy in DAH. DAH was induced by intraperitoneal (IP) injection of pristane in C57BL/6J (B6) mice. Mice were treated with 100 ng/g bodyweight of either Serp-1 as native 55 kDa secreted glycoprotein, or as Serp-1m5, or saline controls after inducing DAH. Treatments were repeated daily for 14 days (6 mice/group). Serp-1 partially and Serp-1m5 significantly reduced pristane-induced DAH when compared with saline as assessed by gross pathology and H&E staining (Serp-1, p = 0.2172; Serp-1m5, p = 0.0252). Both Serp-1m5 and Serp-1 treatment reduced perivascular inflammation and reduced M1 macrophage (Serp-1, p = 0.0350; Serp-1m5, p = 0.0053), hemosiderin-laden macrophage (Serp-1, p = 0.0370; Serp-1m5, p = 0.0424) invasion, and complement C5b/9 staining. Extracellular urokinase-type plasminogen activator receptor positive (uPAR+) clusters were significantly reduced (Serp-1, p = 0.0172; Serp-1m5, p = 0.0025). Serp-1m5 also increased intact uPAR+ alveoli in the lung (p = 0.0091). In conclusion, Serp-1m5 significantly reduces lung damage and hemorrhage in a pristane model of SLE DAH, providing a new potential therapeutic approach.

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“…While we were preparing this manuscript, a similar work on TMPD-induced lupus mouse model using Irf8 −/− mice came out although they focused on a pathological role of inflammatory monocytes in diffuse alveolar hemorrhage [ 43 ]. They demonstrated that the infiltration of Ly6C high monocytes and the upregulation of IFN-inducible genes were diminished in the absence of Irf8.…”

Section: Discussionmentioning

confidence: 99%

“…They demonstrated that the infiltration of Ly6C high monocytes and the upregulation of IFN-inducible genes were diminished in the absence of Irf8. They also demonstrated that hypergammaglobulinemia, ANAs, anti-U1RNP Abs, and glomerulonephritis were all markedly reduced in Irf8 −/− mice after TMPD treatment [ 43 ]. These data are consistent with our data.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory monocyte-derived dendritic cells mediate autoimmunity in murine model of systemic lupus erythematosus

Miyagawa

Tagaya

Ozato

et al. 2020

Journal of Translational Autoimmunity

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Using a mouse model of systemic lupus erythematosus (SLE), we recently demonstrated that the two major manifestations of SLE are mechanistically independent because the type I IFN pathway leads to the autoantibody production whereas the NF-κB activation is sufficient for the development of glomerulonephritis. To further advance our understandings on the molecular pathways regulating the development of SLE, we studied the role of IRF8 because it controls both type I IFN and NF-κB pathways and saw that IRF8-deficient mice failed to develop either glomerulonephritis or the autoantibody production. Furthermore, these genetically engineered mice prompted us to realize the important role of Ly6C high inflammatory monocytes in the development of SLE. These monocytes migrate to the peritoneal cavity in WT and IRF7-deficient mice but not in IRF8-deficient mice, and there they produce both type I IFN and proinflammatory cytokines in WT mice, while in IRF7-deficient mice they only produce proinflammatory cytokines. Upon migration to the spleen, Ly6C high inflammatory monocytes differentiate into dendritic cells (DCs) which are capable of producing proinflammatory cytokines in response to dsDNA autoantigen. Collectively, type I IFN produced from inflammatory monocytes/monocyte-derived DCs might be essential for autoantibody production whereas proinflammatory cytokines produced from them might mediate tissue damages in this model. Our study reveals a specialized role for monocyte-derived antigen presenting cells in autoimmunity. Plasticity of monocyte might play an important role not only in the pathogenesis of the disease but also in flare-ups of the disease.

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High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage

Cited by 20 publications

References 62 publications

Ly6cLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation

Ly6cLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation

PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion

Inflammatory monocyte-derived dendritic cells mediate autoimmunity in murine model of systemic lupus erythematosus

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