Interestingly, Rab GTPases in immune cells are recruited differentially to phagosomes and other cellular organelles based on cell-type and extracellular stimuli [114,115]. GNE-272 which are produced by activated B cells [4]. Human monocytes have been subdivided into different populations based on the surface expression of CD14 and CD16. CD14+ classical monocytes have GNE-272 been observed to be phagocytic with decreased inflammatory characteristics, whilst CD16+ non-classical monocytes have been reported to display inflammatory characteristics and display properties for antigen presentation [5]. Activation of immune cells is usually a healthy response providing to protect and repair the body, however, chronic activation and therefore chronic inflammation is usually deleterious and damaging. LRRK2 is usually a largely ubiquitously expressed protein, and is most abundant in the brain, kidney and lungs. However, increased expression in immune cells, specifically in response to pro-inflammatory signals, has been observed in many immune cell types, strongly implicating LRRK2 as a regulator of the immune response. Increases in mRNA and protein expression have been observed in response to interferon- (IFN-) treatment in human B cells, T cells, macrophages [6C9] and non-classical monocytes [9]. Similar increases in LRRK2 protein expression have been observed in response to the toll-like receptor 4 (TLR4) ligand, lipopolysaccharide (LPS) in bone-marrow-derived macrophages (BMDMs) [10] and main murine-microglia [11] and the cytokine IL-1 [12] in human umbilical vein endothelial cells (HUVECs). Microglia have also been shown to up-regulate LRRK2 protein expression following cranial injection with LPS, as well as increased kinase activity [11]. It has been reported that PD-associated mutations exacerbate LRRK2 expression levels in response to inflammatory stimuli, suggesting a role of LRRK2 in immune cells in PD [13]. This is supported by the observation Rabbit Polyclonal to MRPS16 that the loss of Lrrk2 decreases pro-inflammatory myeloid cells in the brains of rats and decreases neurodegenerative responses to both LPS and -synuclein [14]. LRRK2 is also up-regulated in unstimulated cells in sporadic-PD neutrophils [15], B cells, T Cells, and CD16+/CD14? non-classical monocytes [7]. Furthermore, inhibition of LRRK2 with multiple kinase inhibitors has been shown to decrease CD14, CD16 and MHC-II expression in human immune cells, suggesting that LRRK2 is usually playing a significant role in the activation of cells in response to inflammatory activation in a kinase-dependent manner [8]. LRRK2 kinase activity in disease The increased kinase activity of LRRK2 mutants has been linked to the pathological function of LRRK2 in disease. However, when considering different diseases, cell types, and mutations, the role of LRRK2 kinase activity may not be quite as simple as originally thought (Table 1). Table?1 Summary of results around the role of LRRK2 kinase activity in disease GNE-272 KOIncreased -synuclein uptake and clearance[18]?Main mouse microgliaKD RNAiKOKONo changes in cytokine release[10]?BMDMsKONo changes in cytokine release[20]?Peripheral myeloidKOKOIncreased Mtb control[24]?Peritoneal macrophagesKOcontrolcontrol[25]?Paneth cellsKOIncreased susceptibility to GS increased bacterial control and survivalKOIncreased colitis severity[22]?BMDMsoverexpressionand for rheumatoid arthritis and IBD [30]. Furthermore, peripheral pro-inflammatory cytokine levels are higher in a percentage of asymptomatic subjects transporting the mutation [16], which consistently increases LRRK2 kinase activity [31-35], suggesting an early role of inflammation in a disease that may be driven by increased kinase levels. Interestingly, systemic LPS administration triggers significant increases in peripheral cytokines in mice expressing that exacerbate neuroinflammation in the brain, increases LRRK2 expression in neurons and causes neurodegeneration [17]. The mutations, which reside in the GTPase domain name, fail to consistently increase LRRK2 kinase activity, with both increases [35C38] and no changes [33,34,39] reported. The role of LRRK2 kinase GNE-272 activity in inflammation observed in these mice is usually therefore unclear. The effect of LRRK2 kinase inhibitors, LRRK2 knockdown or kinase-dead mutants has resulted in conflicting results in different immune cell types (Table 1). For example, data from.