Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells

Kolev, Martin; West, Erin E.; Kunz, Natalia; Chauss, Daniel; Moseman, E. Ashley; Rahman, Jamilur; Freiwald, Tilo; Balmer, Maria L.; Lötscher, Jonas; Dimeloe, Sarah; Rosser, Elizabeth C.; Wedderburn, Lucy R.; Mayer‐Barber, Katrin D.; Carpenter, Andrea C.; Lavender, Paul; Cope, Andrew; Wang, Luopin; Kaplan, Mariana J.; Moutsopoulos, Niki M.; McGavern, Dorian B.; Holland, Steven M.; Hess, Christoph; Kazemian, Majid; Afzali, Behdad; Kemper, Claudia

doi:10.1016/j.immuni.2020.02.006

Cited by 66 publications

(108 citation statements)

References 73 publications

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“…Given the changes in endothelial processes, and peripheral immune cell response, we hypothesized that the elevated C3a-C3aR-VCAM1 pathway contributes to vascular changes in PS19 mice. Indeed, co-immunofluorescent analysis of cortical vasculature of 9-month-old PS19 mice labelled with CD31 and VCAM1 revealed a significant increase in VCAM1 expression colocalized with CD31 + vasculature, and this phenotype was rescued to control levels by ablating showed that peripheral immune cells elevate intrinsic C3 production following diapedesis into peripheral tissues (43). They suggest a prominent role for the CD4 + T cell interaction (via LFA-1) with endothelia (via ICAM1), but also identify a similar effect in CD8 + T cells stimulated with VCAM1, showing intrinsic upregulation of IFN-γ and C3 (43).…”

Section: C3ar Modulates Vascular Changes In Ps19 Tau Transgenic Micementioning

confidence: 99%

“…Indeed, co-immunofluorescent analysis of cortical vasculature of 9-month-old PS19 mice labelled with CD31 and VCAM1 revealed a significant increase in VCAM1 expression colocalized with CD31 + vasculature, and this phenotype was rescued to control levels by ablating showed that peripheral immune cells elevate intrinsic C3 production following diapedesis into peripheral tissues (43). They suggest a prominent role for the CD4 + T cell interaction (via LFA-1) with endothelia (via ICAM1), but also identify a similar effect in CD8 + T cells stimulated with VCAM1, showing intrinsic upregulation of IFN-γ and C3 (43). Further dissecting this mechanism with respect to CD8+ T cells and VCAM1 could shed light on potential feed-forward mechanisms affecting microglial reactivity during aging.…”

Section: C3ar Modulates Vascular Changes In Ps19 Tau Transgenic Micementioning

confidence: 99%

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Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging

Propson¹,

Roy

Litvinchuk

et al. 2021

Journal of Clinical Investigation

126

115

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Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer's disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelialspecific ablation of C3ar1. Using an in vitro model of the BBB, we identify intracellular Ca 2+ as a downstream effector of C3a-C3aR signaling and a functional mediator of VE-cadherins junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation is also observed in a tau transgenic mouse model. Our studies suggest that heightened C3a-C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contribute to overall neuroinflammation in aging and neurodegenerative disease.

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Section: C3ar Modulates Vascular Changes In Ps19 Tau Transgenic Micementioning

confidence: 99%

Section: C3ar Modulates Vascular Changes In Ps19 Tau Transgenic Micementioning

confidence: 99%

Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging

Propson¹,

Roy

Litvinchuk

et al. 2021

Journal of Clinical Investigation

126

115

View full text Add to dashboard Cite

show abstract

“…This intracellular “complosome” functions independently of serum-associated complement proteins and plays key noncanonical, autocrine roles in both host defense and basic cellular functions 12 , 13 . For example, in CD4+ T cells, transcription of C3 is triggered by integrin signaling during diapedesis and licenses these cells for Th1-type effector functions 14 . Although neutrophils contain intracellular C3 and macrophages transcribe C3 in response to inflammation 15 , a specific role for intracellular C3 in the recruitment and migration of innate immune cells has not yet been described.…”

Section: Introductionmentioning

confidence: 99%

Cell type specific gene expression profiling reveals a role for complement component C3 in neutrophil responses to tissue damage

Houseright

Rosowski

Lam

et al. 2020

Sci Rep

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Tissue damage induces rapid recruitment of leukocytes and changes in the transcriptional landscape that influence wound healing. However, the cell-type specific transcriptional changes that influence leukocyte function and tissue repair have not been well characterized. Here, we employed translating ribosome affinity purification (TRAP) and RNA sequencing, TRAP-seq, in larval zebrafish to identify genes differentially expressed in neutrophils, macrophages, and epithelial cells in response to wounding. We identified the complement pathway and c3a.1, homologous to the C3 component of human complement, as significantly increased in neutrophils in response to wounds. c3a.1−/− zebrafish larvae have impaired neutrophil directed migration to tail wounds with an initial lag in recruitment early after wounding. Moreover, c3a.1−/− zebrafish larvae have impaired recruitment to localized bacterial infections and reduced survival that is, at least in part, neutrophil mediated. Together, our findings support the power of TRAP-seq to identify cell type specific changes in gene expression that influence neutrophil behavior in response to tissue damage.

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“…Enrichment of the complement system in local T cells (Fig. 1c) was notable because a) we have recently identified complement as one of the most highly induced pathways in CD4 + T cells infiltrating into lung tissues 15 , b) SARS-CoV2 is a potent inducer of complement, especially complement factor 3 (C3), in lung epithelial cells 4 and c) others have previously identified the lungs of patients with COVID-19 as a complement-rich environment 16 . C3 is cleaved to generate activation fragments, of which C3b binds CD46 receptors on T cells.…”

mentioning

confidence: 97%

An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

McGregor

Chauss

Freiwald

et al. 2020

Preprint

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Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner. Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection. The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-γ producing CD4+ T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-γ+ Th1 cells to suppressive IL-10+ Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor. Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4+ T cells were defective in IL-10 production. As proof-of-concept, we show that CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4+ BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyper-inflammation in severe COVID-19.

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Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells

Cited by 66 publications

References 73 publications

Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging

Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging

Cell type specific gene expression profiling reveals a role for complement component C3 in neutrophil responses to tissue damage

An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

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