Abstract:Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exogenous innate or adaptive immune ligands to the infected monocytes/macrophages was required to detect a vitamin D-dependent antimicrobial activity. We investigated whether there is an intrinsic immune response to M. l… Show more
“…4d ). These results indicate that 1,25D produced by macrophages following engagement of TLR1/2 26 , is able to act in an autocrine or intracrine manner to enhance CRIg expression. Fig.…”
Section: Resultsmentioning
confidence: 76%
“…4a ). The TLR1/2 agonist Pam3CSK4, is known to increase the expression of CYP27B1 in macrophages 26 . Using a combination of 25D and Pam3CSK4, we investigated whether treatment with these agents for 24 h causes an increase in CRIg expression.…”
Vitamin D deficiency remains a global concern. This ‘sunshine’ vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg.
“…4d ). These results indicate that 1,25D produced by macrophages following engagement of TLR1/2 26 , is able to act in an autocrine or intracrine manner to enhance CRIg expression. Fig.…”
Section: Resultsmentioning
confidence: 76%
“…4a ). The TLR1/2 agonist Pam3CSK4, is known to increase the expression of CYP27B1 in macrophages 26 . Using a combination of 25D and Pam3CSK4, we investigated whether treatment with these agents for 24 h causes an increase in CRIg expression.…”
Vitamin D deficiency remains a global concern. This ‘sunshine’ vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg.
“…This response is intrinsically activated in M leprae-infected macrophages but blocked through the induction of type I IFN by M leprae. 105 The production of IFNβ and OAS1 in infected monocytes/macrophages in vitro inhibited CYP27B1, which converts inactive prohormone substrate 25-hydroxyvitamin D (25D) to active vitamin D hormone 1α,25-dihydroxyvitamin D required for the antimicrobial response. In conjunction with these in vitro studies, in lesions of lepromatous patients high expression of type I interferon genes and a low expression of CYP27B1 were observed.…”
Section: Vitamin D Not So Healthy For M Lepraementioning
confidence: 99%
“…The vitamin D–dependent pathway is essential for the bacterial killing in M1 macrophages. This response is intrinsically activated in M leprae –infected macrophages but blocked through the induction of type I IFN by M leprae 105 . The production of IFN‐β and OAS1 in infected monocytes/macrophages in vitro inhibited CYP27B1, which converts inactive prohormone substrate 25‐hydroxyvitamin D (25D) to active vitamin D hormone 1α,25‐dihydroxyvitamin D required for the antimicrobial response.…”
Section: Macrophages: Key Determinants Of the Innate Response To M Lementioning
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
“…Macrophages in the Pathogenesis of Leprosy DOI: http://dx.doi.org/10.5772/intechopen.88754 D-mediated antimicrobial pathway via the induction of type I IFN [40]. Although previous studies have demonstrated the activation of antimicrobial pathways in IL-15-differentiated macrophages, there is no study demonstrating how vitamin D status modulates IL-15-differentiated macrophage phenotype and function.…”
Leprosy is a chronic infectious disease caused by the intracellular pathogen Mycobacterium leprae. The disease may present different clinical forms depending on the immunological status of the host. M. leprae may infect macrophages and Schwann cells, and recent studies have demonstrated that macrophages are fundamental cells for determining the outcome of the disease. Skin lesions from patients with the paucibacillary form of the disease present a predominance of macrophages with a pro-inflammatory phenotype (M1), whereas skin lesions of multibacillary patients present a predominance of anti-inflammatory macrophages (M2). More recently, it was shown that autophagy is responsible for the control of bacillary load in paucibacillary macrophages and that the blockade of autophagy is involved in the onset of acute inflammatory reactional episodes in multibacillary cells. So, strategies that aim to induce autophagy in infected macrophages are promising not only to improve the efficacy of multidrug therapy (MDT) but also to avoid the occurrence of reactional episodes that are responsible for the disabilities observed in leprosy patients.2 production of nitric oxide, thus causing peripheral nerve damage characteristic of patients with leprosy [10]. Other studies have shown the ability of M. leprae to induce the production of oxidative mediators and their products, peroxynitrite and nitrotyrosine [11][12][13][14].Studies have demonstrated the ability of M. leprae to interact with a range of scavenger receptors of macrophages culminating in a tolerogenic response profile. The scavenger receptors are membrane receptors whose main function is the removal of molecules and cellular debris from the body, binding through a variety of polyanions, leading to phagocytosis of the target, being found in several cell types such as macrophages [15]. The ability of M. leprae to interact with the CD163 receptor, a scavenger receptor, which, during this interaction, can act as a co-receptor for M. leprae entry in macrophages, has been described [16]. It is known that activation of this receptor is related to the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), leading to the synthesis and increase of the activity of the enzyme heme oxygenase-1 (HO-1), which, through anti-inflammatory and antioxidant pathways, releases interleukin (IL)-10 and generates carbon monoxide, contributing to the polarization of these cells [17][18][19]. Bonilla and colleagues [20] demonstrated that autophagy, a mechanism of metabolic control, regulates the expression of scavenger receptors macrophage receptor with collagenous structure (MARCO) and scavenger receptor type A (SRA-I) that increase phagocytosis and NRF2 activity during Bacillus Calmette-Guérin (BCG) or M. tuberculosis (H37Rv) infection.M. leprae is able to induce macrophage SRA-I and CD36 expression [6] that contributes to the uptake of lipids, culminating in an increase in the uptake and accumulation of oxidized lipids within the macrophages, leading to a fo...
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