LRRK2 is a negative regulator of
            <i>Mycobacterium tuberculosis</i>
            phagosome maturation in macrophages

Härtlová, Anetta; Herbst, Susanne; Peltier, Julien; Rodgers, Angela; Bilkei‐Gorzo, Orsolya; Fearns, Antony; Dill, Brian D.; Lee, Heyne; Flynn, Rowan; Cowley, Sally A.; Davies, Paul; Lewis, Patrick A.; Ganley, Ian G.; Martinez, Jennifer; Alessi, Dario R.; Reith, Alastair D.; Trost, Matthias; Gutiérrez, Maximiliano G.

doi:10.15252/embj.201798694

Cited by 148 publications

(146 citation statements)

References 73 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…Recent data imply that distinct pathways regulate uptake kinetics of different particles as well as phagosome functions in macrophages, and these are further controlled by macrophage activation. It was demonstrated that both the phagocytic receptors (Dill et al , ; Balce et al , ) and pro‐inflammatory (Yates et al , ; Trost et al , ; Ghigo et al , ) and anti‐inflammatory activation (Varin et al , ; Balce et al , ) of macrophages affect phagosome functions and these are regulated by signalling pathways such as kinases (Hartlova et al , ) and E3 ligases (O. Bilkei‐Gorzo, T. Heunis, A. Härtlova, M. Trost, unpublished data ).…”

Section: Discussionmentioning

confidence: 99%

“…However, whether phagosome-associated cell signalling is independent of its role in cargo degradation has not been well understood. Supporting this notion, recent proteomic studies demonstrated that phagosomes are dynamic organelles that change their composition and function in response to infection or inflammation (Trost et al, 2009;Boulais et al, 2010;Dill et al, 2015;Guo et al, 2015;Naujoks et al, 2016;Hartlova et al, 2018). While the regulation of phagosomal maturation in so-called M1 inflammatory macrophages has been extensively studied, the mechanisms facilitating phagosomal maturation in macrophages involved in tissue repair remain poorly understood (Balce et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Triggering MSR1 promotes JNK‐mediated inflammation in IL‐4‐activated macrophages

et al. 2019

Self Cite

View full text Add to dashboard Cite

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL‐4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL‐4‐activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL‐4‐activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti‐inflammatory to a pro‐inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo . Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Triggering MSR1 promotes JNK‐mediated inflammation in IL‐4‐activated macrophages

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…LRRK2 variants are also associated with autoimmune disorders (Witoelar et al, 2017), particularly Crohn's Disease, and with infectious diseases, notably Mycobacterium leprae (Wang et al, 2015;Zhang et al, 2009). LRRK2 expression has also been linked with Mycobacterium tuberculosis infection (Härtlova et al, 2018;Wang et al, 2018). LRRK2 is expressed in a variety of cell lineages, including several immune subsets, notably B cells, neutrophils, monocytes, macrophages and microglia (Atashrazm et al, 2018;Fan et al, 2018;Gardet et al, 2010;Hakimi et al, 2011;Kim et al, 2012;Marker et al, 2012;Moehle et al, 2012;Thévenet et al, 2011) (reviewed in (Lee et al, 2017)).…”

Section: Introductionmentioning

confidence: 99%

LRRK2 is recruited to phagosomes and co-recruits Rab8 and Rab10 in human pluripotent stem cell-derived macrophages

Lee¹,

Flynn²,

Sharma³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

SummaryThe Parkinson’s disease-associated gene, LRRK2, is also associated with immune disorders and infectious disease, and is expressed in immune subsets. Here, we characterise a platform for interrogating the expression and function of endogenous LRRK2 in authentic human phagocytes, using human induced Pluripotent Stem Cell-derived macrophages and microglia. Endogenous LRRK2 is expressed and upregulated by interferon-γ in these cells, including a 187kD cleavage product. Using LRRK2 knockout and G2019S isogenic repair lines, we find that LRRK2 is not involved in initial phagocytic uptake of bioparticles, but is recruited to LAMP1(+)/Rab9(+) ‘maturing’ phagosomes, and LRRK2 kinase inhibition enhances its residency at the phagosome. Importantly, LRRK2 is required for Rab8a and Rab10 recruitment to phagosomes, implying that LRRK2 operates at the intersection between phagosome maturation and recycling pathways in these professional phagocytes.

show abstract

“…Supporting this notion, recent proteomic studies demonstrated that phagosomes are dynamic organelles that change their composition and function in response to infection or inflammation (Boulais et al, 2010, Hartlova et al, 2018, Naujoks et al, 2016, Trost 85 et al, 2009. While the regulation of phagosomal maturation in so-called M1 inflammatory macrophages has been extensively studied, the mechanisms facilitating phagosomal maturation in macrophages involved in tissue repair remains poorly understood (Balce DR., Keizer.…”

Section: Introductionmentioning

confidence: 99%

“…http://dx.doi.org/10.1101/382853 doi: bioRxiv preprint first posted online Aug. 1, 2018;, Trost et al, 2009, Yates et al, 2007 and anti-inflammatory activation (Balce et al, 2011, Varin et al, 2010 of macrophages affects phagosome functions and these are regulated by signalling pathways such as kinases (Hartlova et al, 2018) and E3-335…”

mentioning

confidence: 99%

Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages

Guo

Härtlová

Prescott

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

SummaryAlternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4 activated macrophages. The recruitment of this signalling complex was mediated through K63-polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4 activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63-polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo. Altogether, we identified that MSR1 signals through JNK via K63-polyubiquitylation and provide evidence for the receptor’s involvement in macrophage polarization.

show abstract

LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages

Cited by 148 publications

References 73 publications

Triggering MSR1 promotes JNK‐mediated inflammation in IL‐4‐activated macrophages

Triggering MSR1 promotes JNK‐mediated inflammation in IL‐4‐activated macrophages

LRRK2 is recruited to phagosomes and co-recruits Rab8 and Rab10 in human pluripotent stem cell-derived macrophages

Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages

Contact Info

Product

Resources

About