Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity

Wagener, Matthew; Hoving, J. Claire; Ndlovu, Hlumani; Marakalala, Mohlopheni J.

doi:10.3389/fimmu.2018.00225

Cited by 57 publications

(46 citation statements)

References 61 publications

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“…One of the earliest events that can be detected in RA-development is an innate immune response and the activation of various antigen-presenting cells such as dendritic cells and macrophages [44,45]. The host reaction against Mtb begins with the recognition of pathogen‐associated molecular patterns (PAMPs) by various pattern recognition receptors such as C-type lectin receptors [46], Toll‐like receptors (the C-type lectin receptor CLEC4D and TLR5/8 were found to be upregulated in our meta-analysis, see S2 Table), and the reaction of macrophages and dendritic cells (DC) [47]. It has also been long known that infection with Mtb leads to upregulation of various TLRs, in turn leading to the activation of proinflammatory signals and the production of cytokines [48].…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling meta-analysis reveals novel gene signatures and pathways shared between tuberculosis and rheumatoid arthritis

Badr

Häcker

2019

PLoS ONE

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Tuberculosis (TB) is among the leading causes of death by infectious diseases. An epidemiological association between Mycobacterium tuberculosis infection and autoimmune diseases like rheumatoid arthritis (RA) has been reported but it remains unclear if there is a causal relationship, and if so, which molecular pathways and regulatory mechanisms contribute to it. Here we used a computational biology approach by global gene expression meta-analysis to identify candidate genes and pathways that may link TB and RA. Data were collected from public expression databases such as NCBI GEO. Studies were selected that analyzed mRNA-expression in whole blood or blood cell populations in human case control studies at comparable conditions. Six TB and RA datasets (41 active TB patients, 33 RA patients, and 67 healthy controls) were included in the downstream analysis. This approach allowed the identification of deregulated genes that had not been identified in the single analysis of TB or RA patients and that were co-regulated in TB and RA patients compared to healthy subjects. The genes encoding TLR5, TNFSF10/TRAIL, PPP1R16B/TIMAP, SIAH1, PIK3IP1, and IL17RA were among the genes that were most significantly deregulated in TB and RA. Pathway enrichment analysis revealed ‘T cell receptor signaling pathway’, ‘Toll-like receptor signaling pathway,’ and ‘virus defense related pathways’ among the pathways most strongly associated with both diseases. The identification of a common gene signature and pathways substantiates the observation of an epidemiological association of TB and RA and provides clues on the mechanistic basis of this association. Newly identified genes may be a basis for future functional and epidemiological studies.

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Section: Discussionmentioning

confidence: 99%

Gene expression profiling meta-analysis reveals novel gene signatures and pathways shared between tuberculosis and rheumatoid arthritis

Badr

Häcker

2019

PLoS ONE

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“…In addition to the role of SYK in innate immune signaling pathways (13,14) and inflammatory cytokine secretion (15), recent evidence has indicated the involvement of SYK in a diverse range of biological functions including cellular adhesion, platelet activation, and osteoclast maturation (24). The SYK adaptor protein caspase recruitment domain-containing protein 9 (CARD9) is expressed primarily in lymphoid tissues and contributes to innate immune signaling in response to fungal, viral, and bacterial infections (25)(26)(27). Given that SYK and CARD9 are involved in caspase-8 activation and subsequent IL-1β processing in BMDCs during fungal infection (16), we explored the respective contributions of SYK and CARD9 to disease progression in Pstpip2 cmo mice.…”

Section: Syk But Not Card9 Is Required For Inflammatory Disease Promentioning

confidence: 99%

The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis

Dasari

Geiger

Karki

et al. 2020

Journal of Biological Chemistry

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Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2cmo mice, which carry a missense mutation in the proline–serine–threonine phosphatase–interacting protein 2 (Pstpip2) gene. As cmo disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating cmo. However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in Pstpip2cmo mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain–containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in Pstpip2cmo mice, whereas genetic deletion of Syk completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1β signaling in Pstpip2cmo mice, thereby inducing cmo. These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.

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“…19 M. tuberculosis is able to trigger Dectin-1 signaling in macrophages and activate similar signaling pathways as fungi. 37 During chronic M. tuberculosis infection in mice, the absence of LRRK2 results in enhanced secretion of pro-inflammatory cytokines, with high levels of IFN-γ (IFN, interferon) but an almost complete absence of the Type I IFN-α. 19 Most likely, these results are not a direct consequence of LRRK2 affecting transcription factor activation but might be related to a downstream alteration in pathogen clearance or eventually communication between immune cells.…”

Section: Lrrk2 and Inflammation: Birds Of A Feathermentioning

confidence: 99%

LRRK2 in Infection: Friend or Foe?

Herbst

Gutierrez

2019

ACS Infect. Dis.

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In the field of Parkinson’s disease (PD) research, leucine-rich repeat kinase 2 (LRRK2) remains one of the most enigmatic kinases. LRRK2 pathogenic mutations result in increased kinase activity, making LRRK2 an attractive therapeutic target for PD. For over 10 years, the identification of a bona fide substrate and a physiological function for LRRK2 has been elusive, and only recently, Rab GTPases were identified as substrates for LRRK2 kinase activity. Additionally, LRRK2 gene expression data shows that LRRK2 is expressed at low levels in neurons and at high levels in cells of the immune system. These findings shifted research efforts from neuronal toxicity of LRRK2 mutations to the function of LRRK2 in both vesicle trafficking and the immune system, which has resulted in novel insights into the role of LRRK2 during infection and immunity. In this Perspective, we summarize the latest findings highlighting LRRK2 as a central regulator of vesicular trafficking, infection, immunity, and inflammation, speculating how LRRK2 function could influence neuronal pathology in PD.

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Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity

Cited by 57 publications

References 61 publications

Gene expression profiling meta-analysis reveals novel gene signatures and pathways shared between tuberculosis and rheumatoid arthritis

Gene expression profiling meta-analysis reveals novel gene signatures and pathways shared between tuberculosis and rheumatoid arthritis

The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis

LRRK2 in Infection: Friend or Foe?

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